Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer.

BACKGROUND: In humans, muscle-invasive bladder cancer (MIBC) is highly aggressive and associated with a poor prognosis. With a high mutation load and large number of altered genes, strategies to delineate key driver events are necessary. Dogs and cats develop urothelial carcinoma (UC) with histological and clinical similarities to human MIBC. Cattle that graze on bracken fern also develop UC, associated with exposure to the carcinogen ptaquiloside. These species may represent relevant animal models of spontaneous and carcinogen-induced UC that can provide insight into human MIBC. RESULTS: Whole-exome sequencing of domestic canine (n = 87) and feline (n = 23) UC, and comparative analysis with human MIBC reveals a lower mutation rate in animal cases and the absence of APOBEC mutational signatures. A convergence of driver genes (ARID1A, KDM6A, TP53, FAT1, and NRAS) is discovered, along with common focally amplified and deleted genes involved in regulation of the cell cycle and chromatin remodelling. We identify mismatch repair deficiency in a subset of canine and feline UCs with biallelic inactivation of MSH2. Bovine UC (n = 8) is distinctly different; we identify novel mutational signatures which are recapitulated in vitro in human urinary bladder UC cells treated with bracken fern extracts or purified ptaquiloside. CONCLUSION: Canine and feline urinary bladder UC represent relevant models of MIBC in humans, and cross-species analysis can identify evolutionarily conserved driver genes. We characterize mutational signatures in bovine UC associated with bracken fern and ptaquiloside exposure, a human-linked cancer exposure. Our work demonstrates the relevance of cross-species comparative analysis in understanding both human and animal UC.

A prospective evaluation of the prevalence of thromboemboli and associated hemostatic dysfunction in dogs with carcinoma or sarcoma.

BACKGROUND: Knowledge of the prevalence of thromboemboli and the associated hemostatic status in dogs with carcinoma or sarcoma is unknown and might allow earlier intervention. OBJECTIVES: Estimate prevalence of thromboemboli and their association with hemostatic changes in dogs with carcinomas or sarcomas; estimate predictive values of hemostatic variables for thromboembolic disease in tumor-bearing dogs. ANIMALS: Thirty-two dogs with sarcoma, 30 with carcinoma, 20 healthy age-controlled dogs. METHODS: Prospective cross-sectional study. A hemostasis panel (platelet concentration, thromboelastography, fibrinogen and D-dimer concentration, factor X, VII and antithrombin activity) was performed in all dogs. Tumor-bearing dogs underwent complete post mortem and histopathological evaluation. Comparisons between healthy dogs and tumor-bearing dogs with and without intracavitary hemorrhage; and tumor-bearing dogs with and without microthrombi were analyzed. RESULTS: Thromboembolic disease was identified in 32/62 (52%, 95% CI: 39%-65%) tumor-bearing dogs. Microthrombi were identified in 31/62 (50%, 95% CI: 37%-63%) dogs, 21/31 (68%, 95% CI: 49%-83%) had exclusively intra-tumoral microthrombi, 10/31 (32%, 95% CI: 17%-51%) had distant microthrombi. Macrothrombi were identified in 3 tumor-bearing dogs. Hemostatic changes potentially consistent with overt and non-overt disseminated intravascular coagulation were identified in some tumor-bearing dogs. D-dimer concentrations were significantly higher (P = .02) and platelet concentration significantly lower (P = .03) in tumor-bearing dogs with microthrombi compared to tumor-bearing dogs without microthrombi. D-dimer concentration above 500 ng/mL was 80% sensitive and 41% specific for the prediction of microthrombi presence. CONCLUSION: The high microthrombi prevalence and concomitant hemostatic dysfunction in dogs with carcinomas or sarcomas has not previously been reported, though the clinical importance is unknown. Increased D-dimer concentration might increase suspicion of microthrombi.

Treatment of Canine Oral Melanomas: A Critical Review of the Literature.

Critical appraisal of the available literature for the treatment of canine oral malignant melanoma (OMM) is lacking. This critical review aimed to evaluate the current literature and provide treatment recommendations and possible suggestions for future canine OMM research. PubMed, Web of Science and Google Scholar were searched in June 2021, for terms relevant to treatment of OMM. Inclusion and exclusion criteria were applied and information on clinical response and outcome extracted. Eighty-one studies were included. The overall level of evidence supporting the various canine OMM treatment options was low. The majority of studies included confounding treatment modalities and lacked randomization, control groups and consistency in reporting clinical response and outcomes. Within these limitations, surgery remains the mainstay of therapy. Adjunctive radiotherapy provided good local control and improved median survival times (MST), chemotherapy did not offer survival benefit beyond that of surgery, while electrochemotherapy may offer a potential alternative to radiotherapy. Immunotherapy holds the most promise in extending MST in the surgical adjunctive setting, in particular the combination of gene therapy and autologous vaccination. Prospective, randomized, double-blinded clinical trials, with a lack of confounding factors and reporting based on established guidelines would allow comparison and recommendations for the treatment of canine OMM.

Successful Treatment of Cutaneous Squamous Cell Carcinoma in a Captive Green Iguana (Iguana Iguana).

Reptiles are popular exotic pets and green iguanas (Iguana iguana) are amongst the top ten most popular reptiles. Here we describe a captive 8-year-old female green iguana that was referred for treatment of a non-healing, discharging lesion on the side of the body. The lesion was surgically excised and histopathological analysis revealed an epidermal proliferation of neoplastic keratinocytes, with focal infiltration through the basement membrane, into the underlying superficial dermis. Marked dysplastic changes, characterized by multifocal dyskeratosis and keratin pearl formation were also noted. A diagnosis of cutaneous squamous cell carcinoma (SCC) was made. Two years later, the iguana has shown no signs of recurrence. This is the first report of successful treatment of cutaneous SCC in a green iguana and contributes to the limited knowledge of cutaneous neoplasms in green iguanas.

The prevalence of intra-tumoral and distant thrombi, as well as tumour-cell emboli in canine neoplasia.

Macroscopic thromboembolic disease has been associated with canine neoplasia, whereas prevalence studies of concurrent microthrombi and tumour-cell emboli are lacking. This retrospective study investigated microthrombi and tumour cell emboli by reviewing pathology records of dogs diagnosed with lymphoma, sarcoma, carcinoma and mast cell tumours with a concurrent description of thrombi or emboli. Pathology reports and medical records of cases with either tumour biopsies and/or post mortems with a diagnosis of neoplasia were reviewed for the presence of microthrombi, macrothrombi and/or tumour-cell emboli and the association with tumour type. Of the 28 895 canine cases in the database, 21 252 (73.5%) were antemortem biopsy specimens and 7643 were post mortems (26.5%); 2274 solid tumours were identified, 2107 (92.7%) were antemortem biopsy diagnoses and 167 (7.3%) were post mortem diagnoses. The prevalence of solid tumour types in the database (28 895 cases) was 872 (3.0%) lymphoma, 722 (2.5%) sarcoma, 455 (1.6%) carcinoma and 225 (0.8%) mast cell tumour. The prevalence of microthrombi associated with these tumours was 58/2274 (2.6%). Intra-tumoral microthrombi were reported in 53/2274 (2.3%) cases, the majority in sarcomas (37/53, 69.8%). No macrothrombi were reported. Tumour-cell emboli were identified in 39/2274 (1.7%) cases, 31/39 (79.5%) were extra-tumoral or distant emboli, and carcinoma the most commonly associated tumour (29/39; 74.4%). Microthrombi were reported in 2.6% of cases, the majority in sarcomas and tumour-cell emboli were identified in 1.7% of cases, the majority carcinomas. Prospective investigations are necessary to explore the potential clinical and prognostic implications of microthrombi and tumour-cell emboli in canine neoplasia.

Successful treatment of early cutaneous squamous cell carcinoma with hypofractionated radiation therapy in an African lion (Panthera leo).

Cutaneous squamous cell carcinoma (SCC) is a slow growing but locally invasive neoplasm, most commonly caused by prolonged exposure to ultraviolet (UV) radiation. Whilst SCC accounts for 15% of skin tumours in domesticated cats, cutaneous SCC in non-domesticated felids (apart from captive snow leopards) appears to be uncommon, with only three reports in the literature to date. In this report, a captive African lion (Panthera leo) presented with two ulcerative lesions on the nasal planum. Histopathology of the lesions revealed epidermal keratinocyte dysplasia and neoplastic basal- and supra-basal epithelial cells with dyskeratosis and evidence of basement membrane breaching and dermal invasion, consistent with a diagnosis of SCC. There was also evidence of laminar fibrosis and inflammation of the subjacent dermis suggesting that the SCC most likely resulted from UV-induced neoplastic transformation of the epidermal squamous epithelium following actinic keratosis. The lion was treated with hypofractionated radiation therapy and remained in remission until his death (euthanised 17 months later because of age-related chronic renal failure). This is the first report of cutaneous SCC in a lion with evidence of actinic damage and resolution after radiation therapy.

Spirocerca lupi induced oesophageal neoplasia: Predictors of surgical outcome.

Canine spirocercosis is caused by the nematode Spirocerca lupi. Migration results in oesophageal fibro-inflammatory nodules that may undergo neoplastic transformation. No studies have assessed pre- or post-surgical prognostic indicators in dogs that undergo intervention for S. lupi induced oesophageal neoplasia. This observational, multi-center study aimed to assess the outcome of dogs with Spirocerca induced sarcoma undergoing endoscopic-guided ablation (n = 12) or surgery (n = 18), and identify prognostic indicators. Parameters evaluated included: age, weight, gender, presenting complaints, duration of clinical signs, complete blood count, serum biochemistry, neoplasia size, placement of percutaneous endoscopically-placed gastrostomy tube, histopathological mitotic indices, days to discharge and chemotherapy administration. Kaplan-Meier survival curves showed no difference in survival between ablation and surgery {(median: 73.5 days (range: 0-1511) vs. 108 days (range: 0-1550), respectively (p = 0.982)}. Reduced survival was documented in patients presenting with weight loss (P = 0.027), hypochromasia (MCHC <33 g/dL, P = 0.023) or leucocytosis (>15 × 109/L, P = 0.017) with a hazard ratio of 2.51 (CI95% = 1.071-6.018, P = 0.034), 2.71 (CI95% = 1.10-6.65, P = 0.03) and 4.39 (CI95%: 1.21-15.97, P = 0.025) respectively. In the dogs surviving more than 21 days, Ht <36% and leucocytosis >15.0 × 109/L at presentation were associated with reduced survival (p = 0.016, p = 0.021 respectively) and hazard ratio of 3.29 (CI95% = 1.18-9.2, P = 0.023) and 3.81 (CI95% = 1.15-12.55, P = 0.028) respectively. Intra-intervention-group survival analysis identified increased survival time in dogs receiving chemotherapy, but only within the surgical group (P = 0.02).The hospitalisation time of dogs undergoing ablation (median: 0 days, range: 0-4) was significantly shorter than dogs undergoing surgery (9 days, 1-21) (P < 0.001). In this study, no clear benefit was identified for surgery, thus when ablation is technically possible it should be considered advantageous, as hospitalisation time is significantly shorter. Weight loss, hypochromasia and leucocytosis were identified as long-term prognostic indicators at presentation.

Theileriosis in six dogs in South Africa and its potential clinical significance.

Theileriosis is a tick-borne disease caused by a piroplasma of the genus Theileria that can causeanaemia and thrombocytopenia. Its clinical importance for dogs' remains poorly understood,as only some develop clinical signs. In this study, physical and laboratory findings, treatment and outcomes of six client-owned diseased dogs presented at the Onderstepoort Veterinary Academic Hospital are described retrospectively. In the dogs, Theileria species (n = 4) and Theileria equi (n = 2) were detected by a polymerase chain reaction (PCR)-reverse blothybridisation assay in blood samples, whilst PCR for Babesia, Anaplasma and Ehrlichia were negative. The most common physical findings were pale mucous membranes (five out of six dogs), bleeding tendencies (five out of six dogs) and lethargy (three out of six dogs). All dogs were thrombocytopenic [median 59.5 x 10(9)/L (range 13-199)] and five out of six dogs were anaemic [median haematocrit 18% (range 5-32)]. Bone marrow core biopsies performed in two dogs showed myelofibrosis. Theileriosis was treated with imidocarb dipropionate and the suspected secondary immune-mediated haematological disorders with prednisolone and azathioprine. Five dogs achieved clinical cure and post-treatment PCR performed in three out of five dogs confirmed absence of circulating parasitaemia. An immune-mediated response to Theileria species is thought to result in anaemia and/or thrombocytopenia in diseased dogs with theileriosis. A bleeding tendency, most likely secondary to thrombocytopenia and/or thrombocytopathy, was the most significant clinical finding in these cases. The link between thrombocytopenia, anaemia and myelofibrosis in theileriosis requires further investigation and theileriosis should be considered a differential diagnosis for dogs presenting with anaemia and/or thrombocytopenia in endemic tick-borne disease areas.

Canine spirocercosis-associated extraskeletal osteosarcoma with central nervous system metastasis.

A five-year-old male Boerboel presented for examination, collapsed for an unknown period of time. On clinical examination, multifocal subcutaneous masses and enlarged prescapular lymph nodes as well as neurological deficits that suggested a multifocal neurological syndrome were found. Fine needle aspirates of the prescapular lymph nodes revealed cells suggestive of osteosarcoma. Radiographs showed foci of mineralisation within the soft tissue masses as well as diffuse pulmonary metastasis and a caudodorsal mediastinal mass believed to be a Spirocerca lupi nodule. Computed tomography imaging, necropsy and histopathology confirmed S. lupi oesophageal neoplastic transformation (extraskeletal osteosarcoma), believed to be the primary lesion, and the majority of secondary metastasis to the brain, spine, heart, multiple muscular groups and abdominal organs. This is the first known report of extraskeletal osteosarcoma metastasis to the brain and spinal cord in a dog.

Computed tomographic and radiographic characteristics of aortic lesions in 42 dogs with spirocercosis.

Spirocerca lupi is a common cause of vomiting, regurgitation, and sudden death in dogs that live in tropical or subtropical regions. Sudden death due to aortic rupture may occur with no preceding clinical signs. The purpose of this prospective study was to compare radiographic and computed tomographic (CT) characteristics of aortic lesions in a cohort of 42 dogs with endoscopically confirmed spirocercosis. Dorsoventral and right lateral recumbent thoracic radiographic findings were compared with pre- and postcontrast thoracic CT findings. Aortic mineralization was detected using CT in 18/42 dogs (43%). Three dogs had faint diffuse aortic wall mineralization. Using CT as the reference standard, radiographs had a sensitivity and specificity of 6% and 96%, respectively, for detecting aortic mineralization. A total of 20 aortic aneurysms were detected using CT in 15/42 dogs (36%). Using CT as the reference standard, radiographs had a sensitivity and specificity of 86% and 56%, respectively, for detecting aortic aneurysms. Respiratory motion, aortic displacement by esophageal masses and Spirocerca nodules adjacent to the aorta mimicked aneurysm formation on radiographs. Aortic thrombi were seen in two dogs in postcontrast CT images. Findings from this study indicated that aortic mineralization and aneurysm formation are common in dogs with spirocercosis. Findings also supported the use of pre- and postcontrast CT as effective methods for detecting and characterizing these lesions.