Pharmacokinetics and Early Tumor Response to Conventional Transarterial Chemoembolization with Sorafenib and Doxorubicin in a VX2 Rabbit Tumor Model.

PURPOSE: To investigate the pharmacokinetics (PK) and early effects of conventional transarterial chemoembolization (TACE) using sorafenib and doxorubicin on tumor necrosis, hypoxia markers, and angiogenesis in a rabbit VX2 liver tumor model. MATERIALS AND METHODS: VX2 tumor-laden New Zealand White rabbits (N = 16) were divided into 2 groups: 1 group was treated with hepatic arterial administration of ethiodized oil and doxorubicin emulsion (DOX-TACE), and the other group was treated with ethiodized oil, sorafenib, and doxorubicin emulsion (SORA-DOX-TACE). Animals were killed within 3 days of the procedure. Levels of sorafenib and doxorubicin were measured in blood, tumor, and adjacent liver using mass spectrometry. Tumor necrosis was determined by histopathological examination. Intratumoral hypoxia-inducible factor (HIF) 1α, vascular endothelial growth factor (VEGF), and microvessel density (MVD) were determined by immunohistochemistry. RESULTS: The median intratumoral concentration of sorafenib in the SORA-DOX-TACE group was 17.7 µg/mL (interquartile range [IQR], 7.42-33.5 µg/mL), and its maximal plasma concentration (Cmax) was 0.164 µg/mL (IQR, 0.0798-0.528 µg/mL). The intratumoral concentration and Cmax of doxorubicin were similar between the groups: 4.08 µg/mL (IQR, 3.18-4.79 µg/mL) and 0.677 µg/mL (IQR, 0.315-1.23 µg/mL), respectively, in the DOX-TACE group and 1.68 µg/mL (IQR, 0.795-4.08 µg/mL) and 0.298 µg/mL (IQR, 0.241-0.64 µg/mL), respectively, in the SORA-DOX-TACE group. HIF-1α expression was increased in the SORA-DOX-TACE group than in the DOX-TACE group. Tumor volume, tumor necrosis, VEGF expression, and MVD were similar between the 2 groups. CONCLUSIONS: The addition of sorafenib to DOX-TACE delivered to VX2 liver tumors resulted in high intratumoral and low systemic concentrations of sorafenib without altering the PK of doxorubicin.

Diagnostic accuracy of optical coherence tomography for assessing surgical margins of canine soft tissue sarcomas in observers of different specialties.

OBJECTIVE: To determine the diagnostic accuracy of optical coherence tomography (OCT) to assess surgical margins of canine soft tissue sarcoma (STS) and determine the influence of observer specialty and training. STUDY DESIGN: Blinded clinical prospective study. ANIMALS: Twenty-five dogs undergoing surgical excision of STS. METHODS: In vivo and ex vivo surgical margins were imaged with OCT after tumor resection. Representative images and videos were used to generate a training presentation and data sets. These were completed by 16 observers of four specialties (surgery, radiology, pathology, and OCT researchers). Images and videos from data sets were classified as cancerous or noncancerous. RESULTS: The overall sensitivity and specificity were 88.2% and 92.8%, respectively, for in vivo tissues and 82.5% and 93.3%, respectively, for ex vivo specimens. The overall accurate classification for all specimens was 91.4% in vivo and 89.5% ex vivo. There was no difference in accuracy of interpretation of OCT imaging by observers of different specialties or experience levels. CONCLUSION: Use of OCT to accurately assess surgical margins after STS excision was associated with a high sensitivity and specificity among various specialties. Personnel of all specialties and experience levels could effectively be trained to interpret OCT imaging. CLINICAL SIGNIFICANCE: Optical coherence tomography can be used by personnel of different specialty experience levels and from various specialties to accurately identify canine STS in vivo and ex vivo after a short training session. These encouraging results provide evidence to justify further research to assess the ability of OCT to provide real-time assessments of surgical margins and its applicability to other neoplasms.

Lisdexamfetamine dimesylate (Vyvanse) toxicosis in a dog.

OBJECTIVE: To describe the presentation, management, and postmortem examination findings in a dog with confirmed lisdexamfetamine dimesylate (LDX) toxicosis. CASE SUMMARY: A 3-year-old female neutered mixed breed dog initially presented with neurological signs suspected to be secondary to LDX toxicosis. The dog was treated as typical for amphetamine toxicoses but developed severe respiratory and cardiovascular signs throughout their hospitalization. The progression of the cardiopulmonary signs led to cardiopulmonary arrest, for which CPR was unsuccessful. Postmortem examination exhibited severe hemorrhage throughout multiple organ systems. Toxicology testing confirmed the presence of unaltered LDX and its metabolite, amphetamine. NEW OR UNIQUE INFORMATION PROVIDED: This is the first case report documenting a severe progression of clinical signs and postmortem examination findings in a case of confirmed LDX toxicosis in a dog. Although the patient did not survive treatment, postmortem examination and microscopic evaluation of tissues allowed visualization of the extent of systemic pathophysiology. With prompt treatment, the prognosis of amphetamine toxicosis in dogs is generally considered good; however, this case report demonstrates a severe case in which even prompt and appropriate treatment did not prevent mortality. This suggests a need to establish negative prognostic indicators for which to monitor in cases of amphetamine toxicosis. Finally, this report is also unique in the fact that the LDX toxicosis was confirmed using a toxicological analysis technique not previously described clinically in dogs.

Pathology in Practice.

In collaboration with the American College of Veterinary Pathologists.

Mycobacterium fortuitum abortion in a sow.

Two aborted Chester White pig fetuses were presented to a veterinary diagnostic laboratory in Illinois. Postmortem examination identified no gross abnormalities. Histologic evaluation revealed multifocal necrosis of chorionic epithelial cells, coalescing areas of mineralization in the placenta, and focal accumulations of viable and degenerate neutrophils in the lung. Intra- and extracellular acid-fast bacilli were identified in the lesions in both the placenta and lungs. Bacterial culture of stomach contents yielded heavy growth of Mycobacterium fortuitum, a rapidly growing nontuberculous mycobacterium (NTM), which was further confirmed through whole-genome sequencing. NTM are opportunistic pathogens commonly found in the soil and in contaminated water supplies. In animals, M. fortuitum is typically introduced through cutaneous wounds leading to infections limited to the skin, with systemic infection being uncommon. To our knowledge, abortion caused by M. fortuitum has not been reported previously.

Conventional versus drug-eluting embolic transarterial chemoembolization with doxorubicin: comparative drug delivery, pharmacokinetics, and treatment response in a rabbit VX2 tumor model.

The purpose of this study was to compare intra-tumoral drug delivery, pharmacokinetics, and treatment response after doxorubicin (DOX) conventional (c-) versus drug-eluting embolic (DEE-) transarterial chemoembolization (TACE) in a rabbit VX2 liver tumor model. Twenty-four rabbits with solitary liver tumors underwent c-TACE (n = 12) (1:2 water-in-oil emulsion, 0.6 mL volume, 2 mg DOX) or DEE-TACE (n = 12) (130,000 70-150 µm 2 mg DOX-loaded microspheres). Systemic, intra-tumoral, and liver DOX levels were measured using mass spectrometry up to 7-day post-procedure. Intra-tumoral DOX distribution was quantified using fluorescence imaging. Percent tumor necrosis was quantified by a pathologist blinded to treatment group. Lobar TACE was successfully performed in all cases. Peak concentration (CMAX, µg/mL) for plasma, tumor tissue, and liver were 0.666, 4.232, and 0.270 for c-TACE versus 0.103, 8.988, and 0.610 for DEE-TACE. Area under the concentration versus time curve (AUC, µg/mL ∗ min) for plasma, tumor tissue, and liver were 18.3, 27,078.8, and 1339.1 for c-TACE versus 16.4, 26,204.8, and 1969.6 for DEE-TACE. A single dose of intra-tumoral DOX maintained cytotoxic levels through 7-day post-procedure for both TACE varieties, with a half-life of 1.8 (c-TACE) and 0.8 (DEE-TACE) days. Tumor-to-normal liver DOX ratio was high (c-TACE, 20.2; DEE-TACE, 13.3). c-TACE achieved significantly higher DOX coverage of tumor vs. DEE-TACE (10.8% vs. 2.3%; P = 0.003). Percent tumor necrosis was similar (39% vs. 37%; P = 0.806). In conclusion, in a rabbit VX2 liver tumor model, both c-TACE and DEE-TACE achieved tumoricidal intra-tumoral DOX levels and high tumor-to-normal liver drug ratios, though c-TACE resulted in significantly greater tumor coverage.

Optical coherence tomography imaging of excised canine apocrine gland anal sac adenocarcinoma tumours.

Optical coherence tomography (OCT) is an optical imaging modality that has been investigated for real-time surgical margin evaluation in human breast cancer patients. Previous veterinary OCT studies have been limited to surgical margin imaging for soft tissue sarcoma (STS) tumours. To the authors knowledge, OCT has never been used to characterize or evaluate other types of neoplasia in dogs. The goal of this study was to characterize the OCT imaging appearance of apocrine gland anal sac adenocarcinoma (AGASACA) in excised ex vivo specimens from five client-owned dogs. All excised tissue surgical margins were imaged using a clinical spectral domain OCT system and two to four areas suspicious for incomplete surgical margins were selected. These areas were inked and sections were trimmed for histopathology. This enabled OCT imaging from each area of interest to be compared with corresponding H&E stained histology imaging from the same location. OCT was able to identify the presence of AGASACA at or within 1 mm of the surgical margin in all areas of interest. AGASACA, similar to the previously described canine STS, generated a dense, highly scattering image without any specific textural architecture. This study was able to validate the ability of OCT to accurately identify another type of tumour presence at or close to the surgical margin in the dog. Further study is needed to assess OCT accuracy at identifying other tumour types in dogs to understand its potential clinical applications.

Sylvatic Canine Morbillivirus in Captive Panthera Highlights Viral Promiscuity and the Need for Better Prevention Strategies.

Canine Distemper Virus (CDV) is a multi-host morbillivirus that infects virtually all Carnivora and a few non-human primates. Here we describe a CDV outbreak in an exotic felid rescue center that led to the death of eight felids in the genus Panthera. Similar to domestic dogs and in contrast to previously described CDV cases in Panthera, severe pneumonia was the primary lesion and no viral antigens or CDV-like lesions were detected in the central nervous system. Four tigers succumbed to opportunistic infections. Viral hemagglutinin (H)-gene sequence was up to 99% similar to strains circulating contemporaneously in regional wildlife. CDV lesions in raccoons and skunk were primarily encephalitis. A few affected felids had at least one previous vaccination for CDV, while most felids at the center were vaccinated during the outbreak. Panthera sharing a fence or enclosure with infected conspecifics had significantly higher chances of getting sick or dying, suggesting tiger-tiger spread was more likely than recurrent spillover. Prior vaccination was incomplete and likely not protective. This outbreak highlights the need for further understanding of CDV epidemiology for species conservation and public health.

Evaluating optical coherence tomography for surgical margin assessment of canine mammary tumours.

Optical coherence tomography (OCT) uses near-infrared light waves to generate real-time, high-resolution images on the microscopic scale similar to low power histopathology. Previous studies have demonstrated the use of OCT for real-time surgical margin assessment for human breast cancer. The use of OCT for canine mammary tumours (CMT) could allow intra-operative visualisation of residual tumour at the surgical margins. The purpose of this study was to assess OCT imaging for the detection of incomplete tumour resection following CMT surgery. We hypothesized that the OCT images would have comparable features to histopathological images of tissues at the surgical margins of CMT resections along with a high sensitivity of OCT detection of incomplete surgical excision of CMT. Thirty surgical specimens were obtained from nineteen client-owned dogs undergoing surgical resection of CMT. OCT image appearance and characteristics of adipose tissue, skin, mammary tissue and mammary tumour at the surgical margins were distinct and different. The OCT images of normal and abnormal tissues at the surgical margins were utilized to develop a dataset of OCT images for observer evaluation. The sensitivity and specificity for ex vivo images were 83.3% and 82.0% (observer 1) and 70.0% and 67.9% (observer 2). The sensitivity and specificity for in vivo images were 70.0% and 89.3% (observer 1) and 76.7% and 67.9% (observer 2). These results indicate a potential use of OCT for surgical margin assessment for CMT to optimize surgical intervention and clinical outcomes. Improved training and experience of observers may improve sensitivity and specificity.

Diagnostic accuracy of optical coherence tomography for surgical margin assessment of feline injection-site sarcoma.

The invasive, locally aggressive nature of feline injection-site sarcomas (FISSs) poses a unique challenge for surgeons to obtain complete margins with surgical excision. Optical coherence tomography (OCT), an imaging technology that uses light waves to generate real-time views of tissue architecture, provides an emerging solution to this dilemma by allowing fast, high-resolution scanning of surgical margins. The purpose of this study was to use OCT to assess surgical margins of FISS and to evaluate the diagnostic accuracy of OCT for detecting residual cancer using six evaluators of varying experience. Five FISSs were imaged with OCT to create a training set of OCT images that were compared with histopathology. Next, 25 FISSs were imaged with OCT prior to histopathology. Six evaluators of varying experience participated in a training session on OCT imaging after which each of the evaluators was given a dataset that included OCT images and videos to score on a scale from cancerous to non-cancerous. Diagnostic accuracy statistics were calculated. The overall sensitivity and specificity for classification of OCT images by evaluators were 78.9% and 77.6%, respectively. Correct classification rate of OCT images was associated with experience, while individual sensitivities and specificities had more variation between experience groups. This study demonstrates the ability of evaluators to correctly classify OCT images with overall low levels of experience and training and also illustrates areas where increased training can improve accuracy of evaluators in interpretation of OCT surgical margin images.

Metastatic myxosarcoma in a Quarter Horse gelding.

A 22-y-old Quarter Horse gelding was presented to the University of Illinois Veterinary Teaching Hospital for evaluation of increased heart rate and mild colic signs. Rectal examination revealed a large left perirenal mass. Abdominal ultrasonography further confirmed this finding. Thoracic ultrasonography indicated multifocal irregularities on the pleural surface suggestive of consolidation and possibly masses in the lungs. The animal was euthanized. Autopsy findings included a large, firm, expansile, gelatinous retroperitoneal mass that surrounded both kidneys, as well as nodules with similar morphology in the lungs, liver, intestinal mesentery, cecum, and caudal mesenteric artery. Histologically, the masses were composed of neoplastic stellate-to-spindloid cells in abundant mucinous stroma. Neoplastic cells exhibited strong immunoreactivity for vimentin and were negative for pancytokeratin (A1/A3), CD3, CD20, melan A, and synaptophysin. Mucinous stroma was strongly positive with alcian blue and weakly positive with periodic acid-Schiff histochemical staining. These findings are consistent with metastatic myxosarcoma. Myxosarcoma is a rare neoplasm in horses, and metastasis to tissues other than sentinel lymph nodes has not been described previously to our knowledge.