Opportunities for targeted therapies: trametinib as a therapeutic approach to canine oral squamous cell carcinomas.

Oral tumors are relatively common in dogs, and canine oral squamous cell carcinoma (COSCC) is the most prevalent oral malignancy of epithelial origin. COSCC is locally aggressive with up to 20% of patients showing regional or distant metastasis at the time of diagnosis. The treatment of choice most typically involves wide surgical excision. Although long-term remission is possible, treatments are associated with significant morbidity and can negatively impact functionality and quality of life. OSCCs have significant upregulation of the RAS-RAF-MEK-MAPK signaling axis, and we had previously hypothesized that small-molecule inhibitors that target RAS signaling might effectively inhibit tumor growth and progression. Here, we demonstrate that the MEK inhibitor trametinib, an FDA-approved drug for human cancers, significantly blocks the growth of several COSCC cell lines established from current patient tumor samples. We further show clinical evidence that the drug is able to cause significant tumor regression in some patients with spontaneously occurring COSCC. Given the limited treatment options available and the high rate of owner rejection of these offered options, these findings provide new hope that more acceptable treatment options may soon enter the veterinary clinic.

Trends of regenerative tissue engineering for oral and maxillofacial reconstruction in veterinary medicine.

Oral and maxillofacial (OMF) defects are not limited to humans and are often encountered in other species. Reconstructing significant tissue defects requires an excellent strategy for efficient and cost-effective treatment. In this regard, tissue engineering comprising stem cells, scaffolds, and signaling molecules is emerging as an innovative approach to treating OMF defects in veterinary patients. This review presents a comprehensive overview of OMF defects and tissue engineering principles to establish proper treatment and achieve both hard and soft tissue regeneration in veterinary practice. Moreover, bench-to-bedside future opportunities and challenges of tissue engineering usage are also addressed in this literature review.

Morphological study of pulp cavity anatomy of canine teeth in domestic cats using micro-computed tomography.

An understanding of the pulp cavity anatomy of individual teeth is essential for success during endodontic therapy. The objective of this study was to document pulp cavity anatomy and summarize numerical data of maxillary and mandibular canine teeth of domestic cats using micro-computed tomography (micro-CT). Thirty-nine canine teeth from eleven domestic cat cadaveric specimens were extracted and prepared for scanning. Segmentation of the pulp cavity was performed using the Avizo (v2022.2) software package. The morphological features of the pulp cavity including overall shape, configuration, presence of apical deltas and lateral canals was recorded. A quantitative analysis was performed on thirty-one teeth to explore associations between pulp cavity volume and length, apical delta length, maximum apical delta foramina number and cusp-to-tip length using a linear mixed model. Correlation between pertinent continuous variables was assessed using a Pearson's correlation test. Most pulp cavities exhibited varying curvature and ranged from a cylindrical configuration in the coronal third to an ovoid configuration in the middle to apical third. A ribbon-like flattened canal was observed in 6/31 teeth (19%). All canine teeth depicted an apical delta with various configurations except for two teeth that showed a single canal exiting at the apex. In 15/31 teeth (48%), the primary root canal within the apical delta could be clearly identified and in 16/31 (52%) the primary root canal was indiscernible. The results showed that the pulp cavities of maxillary canine teeth were significantly larger and longer and the cusp-to-tip length was longer, when compared to mandibular teeth. The apical delta length was negatively correlated to the volume of the pulp cavity. No specimens depicted lateral canals. This study revealed that the anatomy of the canine tooth pulp cavity in cats can vary considerably and should be a consideration when performing thorough debridement, shaping and obturation of the endodontic system.

Repair and remodeling of the mandibular head of the condylar process in four immature dogs.

Spontaneous repair and remodeling of the mandibular head of the condylar process is a rarely reported outcome following condylectomy. This clinical report describes the spontaneous repair and subsequent remodeling of the mandibular head of the condylar process in four immature dogs that sustained traumatic injuries, necessitating surgical intervention through arthroplasty via partial or complete condylectomy, or caudal mandibulectomy. In subsequent evaluations, it was observed that all dogs exhibited clinically functional TMJs, as evidenced by an appropriate range of motion. These findings were corroborated by the owners' reports of the patient's normal eating and drinking abilities. Conventional and cone-beam computed tomography studies demonstrated the repair and remodeling of the osseous tissues of the mandibular head of the condylar process. Histopathology was unavailable to assess the novel tissues. No evidence of intraarticular or extraarticular ankylosis or osteoarthritic changes was observed.

Case report: Spontaneous mandibular body regeneration following unilateral subtotal mandibulectomy in a 3-month-old French bulldog.

Objective: To document a case of spontaneous regeneration of the mandibular body following subtotal mandibulectomy in a juvenile dog. Case summary: A 3-month-old male intact French bulldog was presented with papillary oral squamous cell carcinoma located at the dorsal aspect of the molar region of the left mandible. Initial biopsy of the mass was performed by the primary care veterinarian. Complete clinical staging revealed no signs of metastasis. Computed tomographic images of the head showed minimal contrast enhancement of the mass with no signs of periosteal or bone involvement. Subtotal mandibulectomy was performed. Histopathology indicated complete excision of the tumor. The patient returned 8-weeks later for follow up and cleft palate surgical repair, at which time bone was noted in the mandibulectomy area on palpation. Repeat computed tomography of the head revealed complete regeneration of the left mandibular body from the level of the ramus to the mandibular symphysis. No treatment for malocclusion was necessary due to the reformation of a functional mandible. Clinical relevance: The present case demonstrates that spontaneous regeneration of the mandibular body is possible following subtotal mandibulectomy in immature dogs. Subtotal mandibulectomy is a radical procedure that can lead to long term complications including mandibular drift, malocclusion, and oral pain. This case report provides evidence that these sequelae may be mitigated or eliminated in young patients undergoing this procedure.

Microspatial distribution of trace elements in feline dental hard tissues: early life exposure to essential and toxic elements.

Introduction: Trace elements play a key role in dental tissue development, as dental hard tissues accumulate both essential and toxic trace elements during mineralization. Characterization of the spatial accumulation pattern of trace elements may provide insight into exposure to toxic elements over time and to the nature of disease processes affecting the hard dental tissues. Here, we present the first report of the use of laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) to map the microspatial distribution of multiple trace elements, essential and toxic, across feline dental hard tissues. Methods: Eleven teeth were extracted from 8 cats. Nine teeth were from 7 cats diagnosed with idiopathic tooth resorption on intraoral radiographs prior to extraction. Two teeth were included from a cadaver that had no signs of tooth resorption on intraoral radiographs. The normal dental tissue was analyzed from each sample using LA-ICP-MS to map the microspatial distribution of essential and toxic trace elements across feline enamel, dentin, and cementum. Results: Results showed a higher accumulation of barium and strontium in coronal dentin as compared to root dentin. The timing of the accumulation mirrors nursing timelines seen in teeth from human and non-human primates, consistent with barium and strontium being sourced from maternal milk. Results also showed a higher uptake of lead in the coronal dentin, suggesting this lead exposure was likely passed from mother to offspring. Discussion: This work characterizes a baseline for elemental distribution in feline teeth linked to early life exposure to toxic elements such as lead and provides a framework for future studies investigating long-term environmental exposures to trace elements, essential and toxic, and their involvement in feline systemic and dental diseases.

Piezosurgical bone-cutting technology reduces risk of maxillectomy and mandibulectomy complications in dogs.

OBJECTIVE: To report the complication rate of dogs undergoing oral oncological surgery when using a bone-cutting piezoelectric unit for osteotomies. CLINICAL PRESENTATION AND PROCEDURES: Retrospective cohort evaluation of medical records from 2012 through 2022 for canine patients that underwent mandibulectomy or maxillectomy for the treatment of oral neoplasia at the Companion Animal Hospital at Cornell University. Cases were included if osteotomy was performed using a piezoelectric unit. Medical records were then reviewed for documentation of intraoperative hemorrhage and administration of blood products. RESULTS: 41 maxillectomies and 57 mandibulectomies met the inclusion criteria (98 in total). Only 1 (1.02%) case was associated with excessive surgical bleeding requiring administration of blood products. CLINICAL RELEVANCE: Results of this study show that intraoperative hemorrhage requiring the use of blood products during or immediately after a mandibulectomy or maxillectomy is rare when using a piezoelectric unit to perform osteotomies, and is substantially lower than that previously reported when using oscillating saws or other bone-cutting devices for maxillectomies.

Complex Feline Disease Mapping Using a Dense Genotyping Array.

The current feline genotyping array of 63 k single nucleotide polymorphisms has proven its utility for mapping within breeds, and its use has led to the identification of variants associated with Mendelian traits in purebred cats. However, compared to single gene disorders, association studies of complex diseases, especially with the inclusion of random bred cats with relatively low linkage disequilibrium, require a denser genotyping array and an increased sample size to provide statistically significant associations. Here, we undertook a multi-breed study of 1,122 cats, most of which were admitted and phenotyped for nine common complex feline diseases at the Cornell University Hospital for Animals. Using a proprietary 340 k single nucleotide polymorphism mapping array, we identified significant genome-wide associations with hyperthyroidism, diabetes mellitus, and eosinophilic keratoconjunctivitis. These results provide genomic locations for variant discovery and candidate gene screening for these important complex feline diseases, which are relevant not only to feline health, but also to the development of disease models for comparative studies.

The Macroscopic and Radiographic Skull and Dental Pathology of the Tasmanian Devil (Sarcophilus harrisii).

While the gross skull and dental morphology, masticatory biomechanics, dental eruption patterns, and radiographic dental anatomy has been described in the Tasmanian devil (Sarcophilus harrisii), to date no studies have comprehensively examined the prevalence and appearance of pathologic processes affecting their skulls and dentition. As such, the aim of this study was to describe macroscopic and radiographic anatomy and identify the prevalence of anatomic variations and pathological processes in Tasmanian devil dentition and skulls. To do so, anatomical and pathological findings were documented in Tasmanian devil skulls using photography and dental radiography. Assessment of skull trauma, anatomical and developmental abnormalities, periodontitis, endodontic disease, and tooth resorption was performed. A total of 28 Tasmanian devil skulls containing 1,028 teeth were examined. Evidence of postmortem trauma was common. The most common positional abnormality was palatal or buccal rotation of the premolar teeth. While the alveolar bone margin was commonly positioned apically to the cementoenamel junction (98.2%), only 14.2% demonstrated evidence of periodontitis. Tooth fractures were common, affecting 27 skulls, however radiographic signs of endodontic disease were only noted in 4.5% of affected teeth, as was non-inflammatory root resorption (2.0%). A wider root canal width, which was used as a criterion for age determination, was associated with smaller skull dimensions, incompletely erupted teeth, and subjectively less fusion of the mandibular symphysis. Through an improved understanding of what constitutes normal anatomy and the appearance and frequency of pathologic processes that affect the skulls and teeth, this knowledge can help develop a foundation for understanding the oral health and management of live animals for this endangered species.

Preliminary functional analysis of the subgingival microbiota of cats with periodontitis and feline chronic gingivostomatitis.

The subgingival microbial communities of domestic cats remain incompletely characterized and it is unknown whether their functional profiles are associated with disease. In this study, we used a shotgun metagenomic approach to explore the functional potential of subgingival microbial communities in client-owned cats, comparing findings between periodontally healthy cats and cats with naturally occurring chronic periodontitis, aggressive periodontitis, and feline chronic gingivostomatitis. Subgingival samples were subjected to shotgun sequencing and the metagenomic datasets were analyzed using the MG-RAST metagenomic analysis server and STAMP v2.1.3 (Statistical Analysis of Metagenomic Profiles) software. The microbial composition was also described to better understand the predicted features of the communities. The Respiration category in the level 1 Subsystems database varied significantly among groups. In this category, the abundance of V-Type ATP-synthase and Biogenesis of cytochrome c oxidases were significantly enriched in the diseased and in the healthy groups, respectively. Both features have been previously described in periodontal studies in people and are in consonance with the microbial composition of feline subgingival sites. In addition, the narH (nitrate reductase) gene frequency, identified using the KEGG Orthology database, was significantly increased in the healthy group. The results of this study provide preliminary functional insights of the microbial communities associated with periodontitis in domestic cats and suggest that the ATP-synthase and nitrate-nitrite-NO pathways may represent appropriate targets for the treatment of this common disease.

DENTAL DISEASES AND OTHER ORAL PATHOLOGIES OF CAPTIVE JAGUARS (PANTHERA ONCA) FROM BELIZE, CENTRAL AMERICA.

Dental and oral diseases are prevalent in many mammalian species including wild felids. Determining the dental and oral health status of captive animal populations can help establish preventive and therapeutic strategies, leading to improved welfare and conservation efforts. The aim of this study was to assess the prevalence of periodontal disease, endodontic disease, tooth resorption, and other clinically relevant dental and maxillofacial abnormalities in a population of captive jaguars (Panthera onca) using clinical, radiographic, and histopathological findings. Fifteen jaguars, ranging from young adult to geriatric, kept at a private zoo in Belize, Central America, had a detailed oral examination under general anesthesia between January 2015 and March 2019. Periodontitis was present in 3.8% (16/423) of examined teeth and 53.8% (7/13) of jaguars that underwent periodontal probing. Endodontic disease secondary to dentoalveolar trauma was found in 21.0% (89/423) of teeth in 73.3% (11/15) of animals. Tooth resorption, which has not been previously documented in jaguars, affected 1.4% (6/423) of teeth in 13.3% (2/15) of jaguars. Other abnormalities included metallic foreign material (gunshot) identified radiographically in 33.3% (5/15) of jaguars and nontraumatizing malocclusion in 9.1% (1/11) of jaguars that had occlusion evaluated. Much of the oral pathology identified in captive jaguars is suspected to arise from capture and/or captivity-associated behaviors, as suggested by gunshot around the oral cavity, fractures of rostral teeth (canine and incisor teeth), and abrasions consistent with cage-biting on canine teeth. Anesthetized oral examination-including full-mouth intraoral radiographs, periodontal probing, and charting-is recommended for jaguars with clinical signs of oral pain, as well as for routine systemic evaluation.

An Atypical Presentation of a Zygomatic Sialocele in a dog.

A sialocele is an accumulation of salivary fluid due to leakage into the interstitial space surrounding the affected salivary gland and/or its corresponding duct. Reported causes of salivary leakage include trauma, foreign bodies, sialoliths, and neoplasia, but in many cases the etiology is not identified. Clinical signs of sialoceles associated with the zygomatic salivary gland or corresponding duct usually include exophthalmos due to periorbital salivary accumulation, whereas sialoceles associated with the mandibular or sublingual glands or ducts usually manifest as cervical, pharyngeal and/or sublingual salivary accumulation. This case report describes an atypical cervical presentation of a zygomatic sialocele in a dog that resolved after zygomatic sialoadenectomy.

Prevalence, Radiographic, and Demographic Features of Buccal Bone Expansion in Cats: A Cross-Sectional Study at a Referral Institution.

Buccal bone expansion (BBE) refers to bulbous enlargement of the periodontium in domestic cats. The origin of BBE is unknown, and some of its epidemiological, clinical, and radiographic features have not been fully characterized. The purpose of this study was to determine whether specific demographic characteristics are associated with BBE in cats; and whether BBE is associated with other relevant radiographic findings. Pertinent data were collected from archived dental radiographs and electronic medical records of 97 client-owned cats. Results showed that BBE is common in cats presented for evaluation and treatment of dental disease; that breed, sex, and age are not associated with BBE; that BBE is not associated with a pattern of horizontal alveolar bone loss/extrusion or tooth resorption; that a pattern of vertical alveolar bone loss is a typical feature of BBE; and that BBE represents a common cause of canine tooth loss in cats.

Levels of Evidence in Small Animal Dentistry and Oral Surgery Literature Over 40 Years.

Veterinary dentistry and oral surgery are relatively new clinical disciplines that have rapidly evolved in the last few decades. Although clinical standards of care are supported by a growing body of literature, the extent to which peer-reviewed, evidence-based studies have contributed to advancing the practice of dentistry and oral surgery has not been assessed. The purpose of this study was to survey literature on the clinical practice of small animal dentistry and oral surgery published over the past 40 years to evaluate the levels of evidence over time, authorship affiliation, funding, and clinical subdisciplines within the field. A literature search was conducted in PubMed and the identified articles were screened for inclusion. A total of 1,083 articles were included for final analysis. Three reviewers independently assessed and assigned each article to one of nine predetermined study design categories. Systematic reviews and meta-analyses were considered the highest level of evidence, whereas expert opinion and experimental (ex vivo, in vitro, or in silico) studies were deemed the lowest levels of evidence. For statistical analysis and interpretation, study type was dichotomized into high evidence designs from which causal inference and/or associations could be derived, and low evidence designs which were purely descriptive or non-clinical experiments. No statistically significant difference in the distribution of study type was seen over time, with the majority of research in the last 5 years being largely at high risk of bias and descriptive in nature: 80.6% of articles published between 2014 and 2019 were assigned to the low evidence design tier. The type of study was found to differ by author affiliation: high evidence study designs were found more often than expected when author affiliation was multi-institutional or industrial, whereas private practice authorship was underrepresented in the high evidence design tier. To meet the increasing demand for evidence-based studies on the practice of dentistry and oral surgery in dogs and cats, researchers are encouraged to consider study design when testing hypotheses to improve the quality of research.

Frequency of clinical and radiographic evidence of inflammation associated with retained tooth root fragments and the effects of tooth root fragment length and position on oral inflammation in dogs.

OBJECTIVE: To assess the frequency of clinical and radiographic evidence of inflammation (ie, evidence of inflammation) associated with retained tooth root fragments (RTRFs) in dogs and to determine whether evidence of inflammation was affected by RTRF length and position within the alveolar bone. SAMPLE: 148 RTRFs in 66 dogs. PROCEDURES: For each dog, demographic information was recorded, and full-mouth radiographs were obtained and reviewed for RTRFs. For each RTRF, the length of the fragment was measured on intraoral radiographic images, and its location and position relative to the alveolar bone margin were recorded. The presence or absence of evidence of inflammation in association with each RTRF was also recorded. Descriptive data were generated. Generalized linear mixed models were used to identify factors associated with evidence of inflammation around RTRFs. RESULTS: 81 of 148 (54.7%) RTRFs had evidence of inflammation. For every 1-mm increase in RTRF length, the odds of inflammation increased by 17% (OR, 1.17; 95% confidence interval [CI], 1.04 to 1.34; P = 0.009). Odds of inflammation for RTRFs that protruded from the alveolar bone margin were 2.98 (95% CI, 1.02 to 8.72; P = 0.046) and 7.58 (95% CI, 1.98 to 29.08; P = 0.001) times those for RTRFs that were buried and level with the alveolar bone margin, respectively. Tooth root fragment length was a poor predictor of inflammation. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that most RTRFs were associated with evidence of inflammation and supported the current recommendation for extraction of RTRFs whenever feasible.

A multicenter experience using adipose-derived mesenchymal stem cell therapy for cats with chronic, non-responsive gingivostomatitis.

BACKGROUND: The ability of mesenchymal stem cells (MSCs) to modulate immune responses inspired a series of clinical trials addressing oral mucosal inflammation. We previously reported on the safety and efficacy of fresh, allogeneic and autologous, adipose-derived mesenchymal stem cells (ASCs) to treat feline gingivostomatitis (FCGS), an oral mucosal inflammatory disease that shares similarities with human oral lichen planus. METHODS: To meet clinical demand and goals for future commercialization, we determined the feasibility of shipping fresh ASCs to distant clinics and extended our pilot studies to expand safety and efficacy data for shipped and non-shipped ASCs in a cohort of 18 FCGS cats enrolled locally and at a few different locations within the USA. RESULTS: We found that ASCs retained their viability, phenotype, and function after shipment. ASCs administered systemically resulted in a 72% positive response rate, identical to that noted in our previous studies. Cats that responded to ASC therapy had a significant decrease in circulating globulin concentration and histological evidence of decreased CD3+ T cells and CD20+ B cells in the oral mucosa. Responder cats also had significantly decreased percentages of CD8lo cells in blood prior to and at 3 months post-ASC therapy. CD8lo cells may serve as a potential "predictor" for response to systemic ASC therapy. CONCLUSION: Fresh feline ASCs can be successfully shipped and administered to cats with FCGS. ASCs modulate the immune response and demonstrate efficacy for chronic oral mucosal inflammatory lesions that are characterized by CD8+ T cell inflammation and T cell activation. FCGS is a potentially useful naturally occurring large animal model of human oral inflammatory diseases.