Associations Between Dog Breed and Clinical Features of Mammary Epithelial Neoplasia in Bitches: an Epidemiological Study of Submissions to a Single Diagnostic Pathology Centre Between 2008-2021.

Mammary cancer is one of the most common neoplasms of dogs, primarily bitches. While studies have been carried out identifying differing risk of mammary neoplasia in different dog breeds, few studies have reported associations between dog breeds and clinical features such as number of neoplastic lesions found in an individual case or the likelihood of lesions being benign or malignant. Such epidemiological studies are essential as a foundation for exploring potential genetic drivers of mammary tumour behaviour. Here, we have examined associations between breed, age and neuter status and the odds of a diagnosis of a mammary epithelial-origin neoplastic lesion (as opposed to any other histopathological diagnosis from a biopsied lesion) as well as the odds of a bitch presenting with either a single mammary lesion or multiple lesions, and the odds that those lesions are benign or malignant. The study population consisted of 129,258 samples from bitches, including 13,401 mammary epithelial neoplasms, submitted for histological assessment to a single histopathology laboratory between 2008 and 2021.In multivariable analysis, breed, age and neuter status were all significantly associated with the odds of a diagnosis of a mammary epithelial-origin neoplastic lesion. Smaller breeds were more likely to receive such a diagnosis. In cases diagnosed with a mammary epithelial neoplasm, these three factors were also significantly associated with the odds of diagnosis with a malignant lesion and of diagnosis with multiple lesions. Notably, while neutered animals were less likely to have a mammary epithelial neoplasm diagnosed, and were less likely to have multiple neoplasms, they were more likely to have malignant disease. Exploration of the patterns of risk of developing malignant disease, or multiple lesions, across individual breeds showed no breed with increased odds of both outcomes. Breeds with altered odds compared to the Crossbreed baseline were either at increased risk of malignant disease and decreased risk of multiple lesions, or vice versa, or they were at significantly altered odds of one outcome with no change in the other outcome. Our analysis supports the hypothesis that age, neuter status and intrinsic biological and genetic factors all combine to influence the biological heterogeneity of canine mammary neoplasia.

Conditional in vivo deletion of LYN kinase has little effect on a BRCA1 loss-of-function-associated mammary tumour model.

LYN kinase is expressed in BRCA1 loss-of-function-dependent mouse mammary tumours, in the cells of origin of such tumours, and in human breast cancer. Suppressing LYN kinase activity in BRCA1-defective cell lines as well as in in vitro cultures of Brca1-null mouse mammary tumours is deleterious to their growth. Here, we examined the interaction between LYN kinase and BRCA1 loss-of-function in an in vivo mouse mammary tumour model, using conditional knockout Brca1 and Lyn alleles. Comparison of Brca1 tumour cohorts showed little difference in mammary tumour formation between animals that were wild type, heterozygous or homozygous for the conditional Lyn allele, although this was confounded by factors including incomplete Lyn recombination in some tumours. RNA-sequencing analysis demonstrated that tumours with high levels of Lyn gene expression had a slower doubling time, but this was not correlated with levels of LYN staining in tumour cells themselves. Rather, high Lyn expression and slower tumour growth were likely a result of B-cell infiltration. The multifaceted role of LYN indicates that it is likely to present difficulties as a therapeutic target in breast cancer.

Epidemiology of mammary tumours in bitches under veterinary care in the UK in 2016.

BACKGROUND: There is limited information on the epidemiology of canine mammary tumours. This study aimed to estimate the incidence and risk factors for mammary tumours in UK bitches. METHODS: A nested case-control study was conducted within VetCompass to estimate the frequency and risk factors for clinically diagnosed mammary tumours during 2016 (VetCompass study). A second case-control study explored further breed associations for cases confirmed histopathologically compared to the VetCompass controls (laboratory study). Multivariable logistic regression was used to evaluate associations between risk factors and mammary tumours. RESULTS: The incidence of mammary tumours was 1340.7/100,000 per year (95% confidence interval: 1198.1-1483.3). A total of 222 clinical cases (VetCompass study) and 915 laboratory cases (laboratory study) were compared to 1515 VetCompass controls in the two analyses. In the VetCompass study, Springer and Cocker Spaniels, Boxers, Staffordshire Bull Terriers and Lhasa Apsos had increased odds of developing mammary tumours. Neutering was associated with reduced odds, while odds increased with increasing age and a history of pseudopregnancy. In the laboratory study, increasing age was associated with greater odds of mammary tumours, and the breeds most at risk were similar to those identified in the VetCompass study. LIMITATIONS: The timing of neutering was not consistently available. Comparing laboratory cases to VetCompass controls provided only exploratory evidence for the breed associations identified. CONCLUSIONS: The study provides an update on the frequency of canine mammary tumours.

Dog breeds and body conformations with predisposition to osteosarcoma in the UK: a case-control study.

BACKGROUND: Osteosarcoma is an aggressive and painful bone neoplasm in dogs. Previous studies have reported epidemiological associations suggesting that large body mass, long bone length and the genetics of certain breeds including the Rottweiler are associated with elevated osteosarcoma risk. However, these studies were often limited by selection bias and confounding factors, and have rarely offered insights into breed-associated protection for osteosarcoma. The current study includes 1756 appendicular and axial osteosarcoma cases presenting to VPG Histology (Bristol, UK) compared against a control population of 905,211 dogs without osteosarcoma from primary care electronic patient records in the VetCompass™ dataset. METHODS AND STUDY DESIGN: Retrospective, case-control study. Multivariable logistic regression analysis explored associations between demographic risk factors (including breed, chondrodystrophy, age, sex/neuter status, skull-shape, and body mass) and osteosarcoma of all anatomical sites. RESULTS: We identified several breeds with increased and reduced odds of osteosarcoma. At highest risk were the Rottweiler and Great Dane, with > 10 times the odds of osteosarcoma compared with crossbreds, and the Rhodesian Ridgeback, which has not featured in previous lists of at-risk breeds for osteosarcoma, and had an odds ratio of 11.31 (95% confidence interval 7.37-17.35). Breeds at lowest risk of osteosarcoma (protected breeds) included the Bichon Frise, the French Bulldog and the Cavalier King Charles Spaniel, all with odd ratios of less than 0.30 compared with crossbreds. Body mass was strongly associated with osteosarcoma risk; dogs over 40 kg exhibited osteosarcoma odds of 45.44 (95% confidence interval 33.74-61.20) compared with dogs less than 10 kg. Chondrodystrophic breeds had an osteosarcoma odds ratio of 0.13 (95% confidence interval 0.11-0.16) compared with non-chondrodystrophic breeds. CONCLUSIONS: This study provides evidence of strong breed-associated osteosarcoma risk and protection, suggesting a genetic basis for osteosarcoma pathogenesis. It highlights that breeds selected for long legs/large body mass are generally overrepresented amongst at-risk breeds, whilst those selected for short leg length/small body mass are generally protected. These findings could inform genetic studies to identify osteosarcoma risk alleles in canines and humans; as well as increasing awareness amongst veterinarians and owners, resulting in improved breeding practices and clinical management of osteosarcoma in dogs.

Canine Gastric Carcinomas: A Histopathological and Immunohistochemical Study and Similarities with the Human Counterpart.

Canine gastric carcinoma (CGC) affects both sexes in relatively equal proportions, with a mean age of nine years, and the highest frequency in Staffordshire bull terriers. The most common histological subtype in 149 CGC cases was the undifferentiated carcinoma. CGCs were associated with increased chronic inflammation parameters and a greater chronic inflammatory score when Helicobacter spp. were present. Understanding the molecular pathways of gastric carcinoma is challenging. All markers showed variable expression for each subtype. Expression of the cell cycle regulator 14-3-3σ was positive in undifferentiated, tubular and papillary carcinomas. This demonstrates that 14-3-3σ could serve as an immunohistochemical marker in routine diagnosis and that mucinous, papillary and signet-ring cell (SRC) carcinomas follow a 14-3-3σ independent pathway. p16, another cell cycle regulator, showed increased expression in mucinous and SRC carcinomas. Expression of the adhesion molecules E-cadherin and CD44 appear context-dependent, with switching within tumor emboli potentially playing an important role in tumor cell survival, during invasion and metastasis. Within neoplastic emboli, acinar structures lacked expression of all markers, suggesting an independent molecular pathway that requires further investigation. These findings demonstrate similarities and differences between dogs and humans, albeit further clinicopathological data and molecular analysis are required.

Cerebral Microangiopathy in Two Dogs with Cutaneous and Renal Glomerular Vasculopathy.

Cutaneous and renal glomerular vasculopathy (CRGV) is an emerging disease in the UK, but its aetiology remains unclear. It is considered a thrombotic microangiopathy (TMA) in which the kidney and skin are the most commonly affected organs. We now document two cases of CRGV with brain lesions, which may have accounted for neurological signs displayed by these animals. The histopathological brain lesions were similar to TMA lesions in humans with thrombotic thrombocytopaenic purpura (TTP) and complement-mediated haemolytic uraemic syndrome (CM-HUS), in which the neurological signs are more associated with TMA than with any systemic disease or electrolyte imbalance. Fibrinoid necrosis in brain arterioles and associated lesions in these dogs were similar to those in human CM-HUS, indicating that the alternative complement pathway may play an important role in the pathophysiology of CRGV.

Evaluation of the histopathological extent of neoplastic infiltration in intestinal tumours in cats.

With the exception of intestinal lymphoma, surgery is the most commonly recommended treatment for solitary feline intestinal tumours. However, there is a lack of evidence to substantiate resection margin recommendations for these tumours. The aim of this study was to add knowledge concerning resection margins for discrete intestinal masses in cats. Thirty confirmed feline intestinal tumours removed at veterinary centres across the UK from March 2017 to March 2018 underwent histological assessment at the palpable edge of the intestinal tumour and then at every 1 cm increment to the surgeon-cut tissue border in oral, aboral and mesenteric directions. Histological margin recommendations were developed for carcinoma and lymphoma tumour types and non-lymphoma intestinal tumours collectively. Seventeen intestinal lymphomas, nine carcinomas, two sarcomas and two mast cell tumours were evaluated in this study. Seven of the nine intestinal carcinomas would have been completely removed with histological margins of 4 cm in oral and aboral directions. Both sarcomas and one mast cell tumour would have been removed in their entirety with 4 cm histological margins in oral and aboral directions. There was extensive and varied microscopic invasion of intestinal tissue away from discrete intestinal lymphomas in the majority of the cases in this study. There is increasing evidence in veterinary as well as human literature supporting the role of surgical resection in the treatment of discrete intestinal lymphoma. If surgery is to be considered this study supports the removal of the gross tumour only. A histological margin of 4 cm should be considered, where possible, for intestinal masses other than lymphomas.

Evaluation of the extent of neoplastic infiltration in small intestinal tumours in dogs.

There is currently a lack of evidence-based guidance when determining surgical margins for small intestinal tumours in dogs. The purpose of this study is to help the surgeon make informed clinical decisions about margins when confronted with a small intestinal mass. Twenty-seven canine small intestinal tumours were histologically diagnosed and then had further histological assessment at every centimeter from the edge of the palpable tumour to the surgical margin in oral, aboral and mesenteric directions. In all 10 carcinomas a 3 cm tissue margin in oral, aboral and mesenteric directions would have resulted in complete tumour resection. In all 11 sarcomas a 2 cm tissue margin in oral, aboral and mesenteric directions would have resulted in complete tumour resection. Five of the six intestinal lymphomas would have required tissue margins of 4 cm or more for complete resection. Of the 21 non-lymphoma tumours assessed in this study, complete resection was achieved in all 21 (100%) with tissue margins at 3 cm from the palpable edge of the mass, 20 (95%) with tissue margins at 2 cm from the palpable edge of the mass, and 16 (76%) with tissue margins at 1 cm from the palpable edge of the mass in oral and aboral directions. All non-lymphoma canine small intestinal masses will be completely resected when tissue margins are 3 cm from the palpable edge of the mass in oral and aboral directions after fixation in formalin.

Facilitating the initiation of the physician's professional identity: Cornell's urban semester program.

Calling for major reform in medical education, the Carnegie Institute report 'Educating Physicians' espoused the importance of assisting student trainees in forming their professional identities. Here, we consider the question: At what educational stage should future physicians begin this process? The literature suggests that the process begins when students matriculate in medical school; we posit, however, that premedical students can begin their proto-professional development as college undergraduates. We describe here the pedagogy of Cornell University's urban semester program (USP), which enables college students to participate in shadowing experiences as part of an integrated structured study programme. USP students report improved communicative competency, changes in their perceptions and attitudes toward medical practice, and powerful influences on their personal and professional development upon completion of the programme. We suggest the solution to the question of 'When and under what conditions should shadowing take place?' is to utilize a structure that combines the exposure of college students to the professional environment with a didactic and self-reflective curriculum, thereby supporting students in their early professional development. We conclude that educational efforts aimed at developing professional identity and behaviour can begin before students enter medical school.

Are matrix and vascular changes involved in the pathogenesis of deep digital flexor tendon injury in the horse?

It was hypothesised that there is increased blood vessel frequency and proteoglycan staining intensity within the distal aspect of the deep digital flexor tendon (DDFT) in horses with chronic foot pain. Samples of the DDFT from three standardised sites from 10 age-matched mature horses, with chronic foot pain (Group L) or with no history of forelimb lameness (Group N), were collected for this study. A histological analysis of haematoxylin and eosin-stained sections focussed on the frequency and location of blood vessels, while safranin 0 fast green staining was used for semi-quantitative assessment of matrix proteoglycan. The frequency and immunoreactivity of endothelial cell-labelled blood vessels were determined using factor VIII immunolocalisation. There was increased frequency of blood vessels (P=0.048) and increased proteoglycan staining intensity (P=0.028) in Group L, compared with Group N. Qualitative micro-anatomical differences in the matrix and tenocytes were noted between Groups N and L. There was reduced factor VIII staining within the vasculature of horses from Group L, compared with Group N. The results suggested that chronic foot pain may be associated with altered DDFT matrix composition, which could be a potential indicator of degenerative change. The increased vascularity may represent a reparative response to a degenerative tendonopathy.