Prognostic clinical and histopathological features of canine cutaneous epitheliotropic T-cell lymphoma.

Canine cutaneous epitheliotropic T-cell lymphoma is a neoplasm with heterogeneous clinical and histopathological presentations. Survival times and responses to therapy are variable, and indicators to predict outcomes are lacking. Clinical and histopathological parameters from 176 archival cases from the University of Pennsylvania and University of Bern (2012-2018) were investigated for associations with clinical outcomes. Histopathological evaluation used digitized whole slide images and QuPath software. Cases included 107 female and 69 male dogs from 48 breeds, with a mean age of 10.4 years. Most common clinical signs were erythema (n = 131), crusting (n = 108), and scaling (n = 102). Affected sites were haired skin (n = 159), lip (n = 74), nasal planum (n = 49), and paw pads (n = 48). The median survival time (MST) was 95 days (1-850). Dogs had 4.26-fold and 2.82-fold longer MST when treated with chemotherapy and prednisone, respectively, than when receiving supportive care. Haired skin involvement (hazard ratio [HR]: 2.039, 95% confidence interval [CI]: 1.180-3.523), erosions/ulcers (HR: 1.871, 95% CI: 1.373-2.548), nodules (HR: 1.496, 95% CI: 1.056-2.118), and crusting (HR: 1.454, 95% CI: 1.061-1.994) were clinical parameters predicting poor outcomes, whereas complete posttherapeutic clinical remission (HR: 0.469, 95% CI: 0.324-0.680) and a stable disease (HR: 0.323, 95% CI: 0.229-0.456) were associated with longer survival. Histopathological features associated with the increased risk of death were extensive infiltration of the panniculus (HR: 2.865, 95% CI: 1.565-4.809), mitotic count ≥7/high-power field (HR: 3.027, 95% CI: 2.065-4.439), cell diameter ≥10.0 µm (HR: 2.078, 95% CI: 1.281-3.372), and nuclear diameter ≥8.3 µm (HR: 3.787, 95% CI: 1.647-8.707).

Canine Oncopanel: A capture-based, NGS platform for evaluating the mutational landscape and detecting putative driver mutations in canine cancers.

Canine cancer, a significant cause of mortality in domestic dogs, is a powerful comparative model for human cancers. Revealing genetic alterations driving the oncogenesis of canine cancers holds great potential to deepen our understanding of the cancer biology, guide therapeutic development, and improve cancer management in both dogs and people. Next generation sequencing (NGS) based-diagnostic panels have been routinely used in human oncology for the identification of clinically-actionable mutations, enabling tailored treatments based on the individual's unique mutation profiles. Here, we report the development of a comprehensive canine cancer gene panel, the Canine Oncopanel, using a hybridization capture-based targeted NGS method. The Canine Oncopanel allows deep sequencing of 283 cancer genes and the detection of somatic mutations within these genes. Vigorous optimization was performed to achieve robust, high-standard performance using metrics of similar cancer panels in human oncology as benchmarks. Validation of the Canine Oncopanel on reference tumour samples with known mutations demonstrated that it can detect variants previously identified by alternative methods, with high accuracy and sensitivity. Putative drivers were detected in over 90% of clinical samples, showing high sensitivity. The Canine Oncopanel is suitable to map mutation profiles and identify putative driver mutations across common and rare cancer types in dogs. The data generated by the Canine Oncopanel presents a rich resource of putative oncogenic driver mutations and potential clinically relevant markers, paving the way for personalized diagnostics and precision medicine in canine oncology.

Increased tumor-infiltrating lymphocyte density is associated with favorable outcomes in a comparative study of canine histiocytic sarcoma.

Histiocytic sarcoma (HS) is a rare and aggressive tumor in humans with no universally agreed standard of care therapy. Spontaneous canine HS exhibits increased prevalence in specific breeds, shares key genetic and biologic similarities with the human disease, and occurs in an immunocompetent setting. Previous data allude to the immunogenicity of this disease in both species, highlighting the potential for their successful treatment with immunotherapy. Quantification of CD3 tumor-infiltrating lymphocytes (TIL) in five cases of human HS revealed variable intra-tumoral T cell infiltration. Due to the paucity of human cases and lack of current model systems in which to appraise associations between anti-tumor immunity and treatment-outcome in HS, we analyzed clinical data and quantified TIL in 18 dogs that were previously diagnosed with localized HS and treated with curative-intent tumor resection with or without adjuvant chemotherapy. As in humans, assessment of TIL in biopsy tissues taken at diagnosis reveal a spectrum of immunologically "cold" to "hot" tumors. Importantly, we show that increased CD3 and granzyme B TIL are positively associated with favorable outcomes in dogs following surgical resection. NanoString transcriptional analyses revealed increased T cell and antigen presentation transcripts associated with prolonged survival in canine pulmonary HS and a decreased tumor immunogenicity profile associated with shorter survivals in splenic HS. Based on these findings, we propose that spontaneous canine HS is an accessible and powerful novel model to study tumor immunology and will provide a unique platform to preclinically appraise the efficacy and tolerability of anti-cancer immunotherapies for HS.

Immunohistochemical evaluation of suspected oral malignant melanoma in cats.

Oral malignant melanoma (OMM) is considered the third most common oral malignant neoplasm in cats, but its variable morphology and frequent lack of melanin pigment make it a diagnostic challenge. Twenty-two cases of cats with malignant oral neoplasms that were diagnosed as OMM or listed OMM as a suspected differential diagnosis on the biopsy report were examined using an immunohistochemistry (IHC) panel for S100, melan-A, PNL2, laminin, CD34, and pan-cytokeratin. Although OMM was suspected (n = 14) or previously diagnosed (n = 8), only 2 cases were immunohistochemically confirmed as OMM. Seven cases were classified as soft tissue sarcoma based on positive expression of CD34 or laminin, and one was classified as carcinoma based on positive expression of pan-cytokeratin. The majority of cases (n = 12) were categorized as unclassified malignant neoplasms because they did not express melan-A, PNL2, laminin, CD34, or pan-cytokeratin; however, a proportion of these did express S100 (n = 7). Long-term prognosis of all 22 cats was poor, with a median survival time of 87 days (range = 2-249 days). Cases with longer survival times (>100 days) were treated with surgery, radiation therapy, or a combination. For feline oral malignant neoplasms thought to be OMM, routine use of IHC is required for an accurate diagnosis.

Collagen molecular phenotypic switch between non-neoplastic and neoplastic canine mammary tissues.

In spite of major advances over the past several decades in diagnosis and treatment, breast cancer remains a global cause of morbidity and premature death for both human and veterinary patients. Due to multiple shared clinicopathological features, dogs provide an excellent model of human breast cancer, thus, a comparative oncology approach may advance our understanding of breast cancer biology and improve patient outcomes. Despite an increasing awareness of the critical role of fibrillar collagens in breast cancer biology, tumor-permissive collagen features are still ill-defined. Here, we characterize the molecular and morphological phenotypes of type I collagen in canine mammary gland tumors. Canine mammary carcinoma samples contained longer collagen fibers as well as a greater population of wider fibers compared to non-neoplastic and adenoma samples. Furthermore, the total number of collagen cross-links enriched in the stable hydroxylysine-aldehyde derived cross-links was significantly increased in neoplastic mammary gland samples compared to non-neoplastic mammary gland tissue. The mass spectrometric analyses of type I collagen revealed that in malignant mammary tumor samples, lysine residues, in particular those in the telopeptides, were markedly over-hydroxylated in comparison to non-neoplastic mammary tissue. The extent of glycosylation of hydroxylysine residues was comparable among the groups. Consistent with these data, expression levels of genes encoding lysyl hydroxylase 2 (LH2) and its molecular chaperone FK506-binding protein 65 were both significantly increased in neoplastic samples. These alterations likely lead to an increase in the LH2-mediated stable collagen cross-links in mammary carcinoma that may promote tumor cell metastasis in these patients.

Modeling molecular development of breast cancer in canine mammary tumors.

Understanding the changes in diverse molecular pathways underlying the development of breast tumors is critical for improving diagnosis, treatment, and drug development. Here, we used RNA-profiling of canine mammary tumors (CMTs) coupled with a robust analysis framework to model molecular changes in human breast cancer. Our study leveraged a key advantage of the canine model, the frequent presence of multiple naturally occurring tumors at diagnosis, thus providing samples spanning normal tissue and benign and malignant tumors from each patient. We showed human breast cancer signals, at both expression and mutation level, are evident in CMTs. Profiling multiple tumors per patient enabled by the CMT model allowed us to resolve statistically robust transcription patterns and biological pathways specific to malignant tumors versus those arising in benign tumors or shared with normal tissues. We showed that multiple histological samples per patient is necessary to effectively capture these progression-related signatures, and that carcinoma-specific signatures are predictive of survival for human breast cancer patients. To catalyze and support similar analyses and use of the CMT model by other biomedical researchers, we provide FREYA, a robust data processing pipeline and statistical analyses framework.

Clinical, histopathologic, and immunohistochemical features of 13 cases of canine gallbladder neuroendocrine carcinoma.

In this retrospective descriptive study, we characterized the clinical, histologic, and immunohistochemical features of 13 cases of canine gallbladder neuroendocrine carcinoma (GB-NEC). Immunohistochemical stains for neuroendocrine (neuron-specific enolase [NSE], chromogranin A, synaptophysin) and gastrin markers were evaluated, and clinicopathologic and follow-up data were obtained for all cases. The average age at diagnosis was 8.9 y, and breeds included 6 Boston Terriers, 2 Bichon Frise, 1 Poodle, 1 English Bulldog, 1 French Bulldog, and 2 mixed-breed dogs. Boston Terriers were overrepresented in this cohort, and therefore a breed predilection is possible. Most dogs were presented with emesis and elevated liver enzyme activities: 13 of 13 had elevated alanine aminotransferase and alkaline phosphatase activities; 8 of 13 had elevated aspartate aminotransferase activity; 7 of 13 had elevated gamma-glutamyl transferase activity. Abdominal ultrasound and/or exploratory surgery revealed a gallbladder mass. All neoplasms had similar histologic features and positive immunoreactivity for NSE, chromogranin A, synaptophysin, and gastrin. Vascular invasion was noted in 8 of 13 neoplasms, and metastasis was present in 6 of 13 cases (4 hepatic and 2 pulmonary metastases). The median survival time was 3.7 y in patients who died; 5 of 8 deaths were directly attributed to the GB-NEC, 3 of which had metastatic spread. GB-NECs have the potential to metastasize; however, surgical excision may be curative in a subset of dogs.

Intratumoral collagen signatures predict clinical outcomes in feline mammary carcinoma.

Breast cancer is the most common cause of cancer-related deaths in women worldwide. Identification of reliable prognostic indicators and therapeutic targets is critical for improving patient outcome. Cancer in companion animals often strongly resembles human cancers and a comparative approach to identify prognostic markers can improve clinical care across species. Feline mammary tumors (FMT) serve as models for extremely aggressive triple negative breast cancer (TNBC) in humans, with high rates of local and distant recurrence after resection. Despite the aggressive clinical behavior of most FMT, current prognostic indicators are insufficient for accurately predicting outcome, similar to human patients. Given significant heterogeneity of mammary tumors, there has been a recent focus on identification of universal tumor-permissive stromal features that can predict biologic behavior and provide therapeutic targets to improve outcome. As in human and canine patients, collagen signatures appear to play a key role in directing mammary tumor behavior in feline patients. We find that patients bearing FMTs with denser collagen, as well as longer, thicker and straighter fibers and less identifiable tumor-stromal boundaries had poorer outcomes, independent of the clinical variables grade and surgical margins. Most importantly, including the collagen parameters increased the predictive power of the clinical model. Thus, our data suggest that similarities with respect to the stromal microenvironment between species may allow this model to predict outcome and develop novel therapeutic targets within the tumor stroma that would benefit both veterinary and human patients with aggressive mammary tumors.

A prospective randomized trial of desmopressin in canine mammary carcinoma.

Metastatic disease represents a serious and often fatal development in patients with solid tumours, including women with breast cancer and dogs with mammary tumours. Therefore, preventing and treating metastatic disease has remained a priority in cancer research. Desmopressin, a synthetic derivative of vasopressin, traditionally used to treat patients with bleeding disorders, has been proposed as a potential anti-metastatic agent due to its effect on haemostasis as well as multiple other anti-proliferative and anti-angiogenic mechanisms. The purpose of this study was to retest desmopressin in dogs with mammary carcinomas. A prospective randomized study was performed. Twenty-four dogs with mammary carcinomas were enrolled; 12 dogs received perioperative desmopressin and 12 received placebo. All dogs underwent standard pre-surgical staging followed by complete resection of all tumours. Intact dogs were spayed. All tumours were graded and classified according to the published guidelines. Follow-up was performed every 4 months the first year and every 6 months thereafter. Necropsies were requested on all dogs. There was no difference in time to primary metastasis or survival between desmopressin treated dogs and the placebo arm (P = .43 and .73, respectively). The distribution of negative prognostic factors, including tumour grade, stage, and high vs low bioscore (refined flexible bioscoring) category between arms was not statistically different, even though more dogs in the placebo arm had grade 3 tumours and high bioscores. Based on the results of this study, perioperative desmopressin does not prevent metastasis in dogs with mammary carcinomas.

Molecular subtypes in canine hemangiosarcoma reveal similarities with human angiosarcoma.

Angiosarcoma (AS) is a rare neoplasm with limited treatment options and a poor survival rate. Development of effective therapies is hindered by the rarity of this disease. Dogs spontaneously develop hemangiosarcoma (HSA), a common, histologically similar neoplasm. Metastatic disease occurs rapidly and despite chemotherapy, most dogs die several months after diagnosis. These features suggest that HSA might provide a tractable model to test experimental therapies in clinical trials. We previously reported whole exome sequencing of 20 HSA cases. Here we report development of a NGS targeted resequencing panel to detect driver mutations in HSA and other canine tumors. We validated the panel by resequencing the original 20 cases and sequenced 30 additional cases. Overall, we identified potential driver mutations in over 90% of the cases, including well-documented (in human cancers) oncogenic mutations in PIK3CA (46%), PTEN (6%), PLCG1(4%), and TP53 (66%), as well as previously undetected recurrent activating mutations in NRAS (24%). The driver role of these mutations is further demonstrated by augmented downstream signaling crucial to tumor growth. The recurrent, mutually exclusive mutation patterns suggest distinct molecular subtypes of HSA. Driver mutations in some subtypes closely resemble those seen in some AS cases, including NRAS, PLCG1, PIK3CA and TP53. Furthermore, activation of the MAPK and PI3K pathways appear to be key oncogenic mechanisms in both species. Together, these observations suggest that dogs with spontaneous HSA could serve as a useful model for testing the efficacy of targeted therapies, some of which could potentially be of therapeutic value in AS.

Primary Hemangiosarcoma of the Falciform Fat in Seven Dogs (2007-2015).

Canine hemangiosarcoma (HSA), a malignant neoplasm of vascular endothelial or bone marrow progenitor cell origin, most often affects the spleen, heart, and liver and typically has an aggressive biologic behavior. Canine HSA arising from the falciform fat/ligament represents a rare anatomic variant, with only two reports in the veterinary literature. In this study, we describe the clinical presentation, treatment, and outcome of seven dogs with primary HSA of the falciform ligament. Histologic grade and mitotic score were not significantly associated with outcome. All dogs had the primary tumor surgically excised except for one diagnosed at necropsy. Median overall survival for all dogs diagnosed prior to necropsy was 339 days, and the 1 yr survival rate was 50%. Four dogs were treated with adjuvant chemotherapy and had a significantly longer median overall survival (394 versus 83 days) than those that did not (P = .018). Dogs with HSA of the falciform ligament may have improved 1 yr survival rates and longer median survival time compared with dogs with HSA in more common visceral locations.

Toxicity and Efficacy Evaluation of an Adeno-Associated Virus Vector Expressing Codon-Optimized RPGR Delivered by Subretinal Injection in a Canine Model of X-linked Retinitis Pigmentosa.

Applied Genetic Technologies Corporation (AGTC) is developing a recombinant adeno-associated virus (rAAV) vector AGTC-501, also designated rAAV2tYF-GRK1-hRPGRco, to treat X-linked retinitis pigmentosa (XLRP) in patients with mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. The vector contains a codon-optimized human RPGR cDNA (hRPGRco) driven by a photoreceptor-specific promoter (G protein-coupled receptor kinase 1 [GRK1]), and is packaged in an AAV2 capsid variant with three surface tyrosine residues changed to phenylalanine (AAV2tYF). We conducted a toxicity and efficacy study of this vector administered by subretinal injection in the naturally occurring RPGR mutant (X-linked progressive retinal atrophy 2 [XLPRA2]) dog model. Sixteen RPGR mutant dogs divided into four groups of three to five animals each received either a subretinal injection of 0.07 mL of AGTC-501 at low (1.2 × 1011 vector genome [vg]/mL), mid (6 × 1011 vg/mL), or high dose (3 × 1012 vg/mL), or of vehicle control in the right eye at early-stage disease. The left eye remained untreated. Subretinal injections were well tolerated and were not associated with systemic toxicity. Electroretinography, in vivo retinal imaging, and histological analysis showed rescue of photoreceptor function and structure in the absence of ocular toxicity in the low- and mid-dose treatment groups when compared with the vehicle-treated group. The high-dose group showed evidence of both photoreceptor rescue and posterior segment toxicity. These results support the use of AGTC-501 in clinical studies with patients affected with XLRP caused by RPGR mutations and define the no-observed-adverse-effect level at 6 × 1011 vg/mL.

Clinical and histopathological classification of feline intraocular lymphoma.

This retrospective study aimed to describe and classify cats with intraocular lymphoma, determine the proportion of cases with presumed solitary ocular lymphoma (PSOL) compared with ocular manifestations of multicentric disease and assess the clinical outcomes of these patients. One hundred seventy-two cases identified through biopsy submissions were reviewed histologically; 163 of these cases were subtyped according to the WHO classification system. Cases were categorized as having PSOL or ocular lymphoma with suspected systemic involvement (SSI) based on submission forms and follow-up data. The majority of cases exhibited concurrent uveitis (75%) and secondary glaucoma (58%). Diffuse large B-cell lymphoma was the most common subtype (n = 86; 53%), followed by peripheral T-cell lymphoma (n = 44; 27%). Other subtypes included anaplastic large T- (n = 8; 5%) and B-cell (n = 4; 2.5%) lymphomas, and 15 cases (9%) were negative for all immunohistochemical markers. In sixty-nine cases (40%), adequate clinical data and sufficient survival data were obtained to distinguish PSOL from SSI. PSOL comprised the majority of cases (64%), while 36% had SSI. When covarying for age at diagnosis, the median survival time was significantly higher (P = 0.003) for cases of PSOL (154 days) versus those with SSI (69 days); hazards ratio of 0.47 for PSOL (95% CI: 0.241-0.937). The subtype of lymphoma did not affect survival time. Cats with PSOL represent a greater proportion of the disease population, and this subset of cats with intraocular lymphoma has a better clinical outcome.

The estrogen effect; clinical and histopathological evidence of dichotomous influences in dogs with spontaneous mammary carcinomas.

The purpose of this study was to investigate the associations and explore the relationships between hormonal factors (serum estrogen, estrogen receptors and ovariohysterectomy) and other clinical/histological prognostic factors and their impact on outcome in dogs with mammary carcinomas. Data from two separate prospective studies on dogs with spontaneous mammary carcinomas were used for this research. All dogs underwent standardized diagnostic testing, staging, surgery and follow-up examinations. Serum estrogen was analyzed by competitive enzyme immunoassay or radioimmunoassay, and tumor estrogen receptor (ER) expression was analyzed by immunohistochemistry. A total of 159 dogs were included; 130 were spayed and 29 remained. High serum estrogen was associated with an overall longer time to metastasis (p = 0.021). When stratifying based on spay group, the effect was only significant in spayed dogs, (p = 0.019). Positive tumor ER expression was also associated with a longer time to metastasis (p = 0.025), but similar to above, only in dogs that were spayed (p = 0.049). Further subgroup analysis revealed that high serum estrogen was significantly associated with improved survival in dogs with ER positive tumors, but only in spayed dogs (p = 0.0052). Interestingly, the effect of spaying was the opposite in dogs with ER negative tumors; here, intact dogs with high serum estrogen but ER negative tumors had a significantly longer time to metastasis (p = 0.036). Low serum estrogen was associated with increased risk for the development of non-mammary tumors in the post-operative period (p = 0.012). These results highlight the dual effect of estrogen in cancer: Estrogen acts as a pro-carcinogen in ER positive mammary tumors, but a may have a protective effect in ER negative tumors, potentially via non-receptor mechanisms. The latter is supported by the decreased risk for non-mammary tumors in dogs with high serum estrogen, and explains the increased incidence of certain non-mammary tumors in in dogs spayed at an early age.

Agreement in Histological Assessment of Mitotic Activity Between Microscopy and Digital Whole Slide Images Informs Conversion for Clinical Diagnosis.

Validating digital pathology as substitute for conventional microscopy in diagnosis remains a priority to assure effectiveness. Intermodality concordance studies typically focus on achieving the same diagnosis by digital display of whole slide images and conventional microscopy. Assessment of discrete histological features in whole slide images, such as mitotic figures, has not been thoroughly evaluated in diagnostic practice. To further gauge the interchangeability of conventional microscopy with digital display for primary diagnosis, 12 pathologists examined 113 canine naturally occurring mucosal melanomas exhibiting a wide range of mitotic activity. Design reflected diverse diagnostic settings and investigated independent location, interpretation, and enumeration of mitotic figures. Intermodality agreement was assessed employing conventional microscopy (CM40×), and whole slide image specimens scanned at 20× (WSI20×) and at 40× (WSI40×) objective magnifications. An aggregate 1647 mitotic figure count observations were available from conventional microscopy and whole slide images for comparison. The intraobserver concordance rate of paired observations was 0.785 to 0.801; interobserver rate was 0.784 to 0.794. Correlation coefficients between the 2 digital modes, and as compared to conventional microscopy, were similar and suggest noninferiority among modalities, including whole slide image acquired at lower 20× resolution. As mitotic figure counts serve for prognostic grading of several tumor types, including melanoma, 6 of 8 pathologists retrospectively predicted survival prognosis using whole slide images, compared to 9 of 10 by conventional microscopy, a first evaluation of whole slide image for mitotic figure prognostic grading. This study demonstrated agreement of replicate reads obtained across conventional microscopy and whole slide images. Hence, quantifying mitotic figures served as surrogate histological feature with which to further credential the interchangeability of whole slide images for primary diagnosis.

Outcomes in 40 cats with discrete intermediate- or large-cell gastrointestinal lymphoma masses treated with surgical mass resection (2005-2015).

OBJECTIVE: To report outcomes in cats with discrete intermediate- and large-cell gastrointestinal (GI) lymphoma masses after surgical resection. STUDY DESIGN: Retrospective clinical case series. ANIMALS: Forty client-owned cats in which intermediate- or large-cell GI lymphoma was diagnosed. METHODS: Records of 40 cats in which discrete intermediate- or large-cell GI lymphoma masses were diagnosed between 2005 and 2015 were reviewed. Cats were included if they survived curative intent surgery and had a known outcome for at least two weeks. Postoperative death was permitted. Data collected included anatomic site, surgical margins, lymphoma subtype, chemotherapy use, and postoperative and long-term outcome (beyond two weeks). RESULTS: Affected sites consisted of small intestines (n = 23), large intestines (n = 9), and stomach (n = 8). Thirty-six of 40 cats survived to discharge, and 31 cats were alive at suture removal. Median long-term follow-up of 22 cats was 111 days (range, 16-1407). Cats that survived to suture removal had a median survival time (MST) of 185 days (95% confidence interval: 72-465). Cats with large intestinal masses lived longer than those with small intestinal or gastric masses whether all cats (MST, 675, 64, 96 days, respectively; P = .03) or only those surviving to suture removal were considered. Complete surgical resection (n = 20) was positively associated with survival (370 vs 83 days, P = .016). CONCLUSION: Most cats in this population survived the perioperative period, with MST similar to those reported historically with medical management. CLINICAL SIGNIFICANCE: Surgical resection may be a reasonable consideration in cats with solitary lymphoma, particularly those with large intestinal masses.

Clinical outcomes, ultrastructure and immunohistochemical features of canine high-grade olfactory neuroblastoma.

Olfactory neuroblastoma (ONB) is a rare intranasal neoplasm in both dogs and humans. Similar clinical presentation and overlapping histologic and immunohistochemical features of ONB with other intranasal neoplasms can make diagnosis and treatment of intranasal neoplasia challenging. Furthermore, in part because of their rarity, there is a lack of reporting on therapeutic regimen for these neoplasms. In humans, initial debulking surgery is usually followed by radiation therapy. Here we report on the histologic, immunohistochemical, and ultrastructural characteristics of canine ONB and report on the clinical progression of cases treated with radiation therapy. In all nine canine ONB examined here, neoplastic cells were arranged in a lobular manner amidst a prominent neurofibrillary matrix and had features consistent with Grade III (high grade) ONB. The neoplastic cells demonstrated positive immunohistochemical staining for TuJ-1, a Class III beta-tubulin neuronal cytoskeletal protein, and variable staining for other markers, including chromogranin, synaptophysin, AE1/AE3 and MAP2. The longest surviving case was treated with a regimen similar to that used in humans, consisting of debulking surgery followed by definitive radiation therapy. Our study found that TuJ-1 is a useful marker for ONB and that radiation therapy, even in cases of advanced disease, may result in prolonged survival.

Co-occurrence of Nasal Polyps and Neoplasms of the Canine Nasal Cavity.

Nasal polyps in dogs are space-occupying soft-tissue masses that have been encountered concurrently with intranasal neoplasia in surgical biopsy specimens. The proportion of nasal polyp co-occurrence with primary nasal tumors was examined, and follow-up biopsies on dogs initially diagnosed with nasal polyp were reviewed. Histologic sections from 321 cases of intranasal neoplasia and 50 cases of nasal polyp from 2004 to 2017 were reviewed. Of the 321 cases of intranasal neoplasia, 51 (16%) had concurrent nasal polyps, and most of these (47/51) had intranasal carcinoma. Twenty-five of the 50 dogs with a primary diagnosis of nasal polyp were rebiopsied, and the diagnoses in these subsequent biopsies were nasal polyp in 15, malignant neoplasm in 9, and intranasal nematode in 1. Nasal polyps occurred frequently in conjunction with nasal carcinoma. In dogs with a diagnosis of nasal polyp, repeat biopsy to reveal possible neoplasia is warranted.

Developing and testing prognostic bio-scoring systems for canine mammary gland carcinomas.

Canine mammary carcinomas (CMC) represent a range of histolopathological subtypes with diverse biological behaviours. Several individual factors, including stage, grade, subtypes and presence of invasion, predict outcome. Less is known how these factors interact and impact prognosis. The purpose of this work was to develop and test comprehensive bio-scoring systems in CMCs. Clinical and histopathological data from 127 dogs with MCs treated through two prospective studies were obtained. All dogs underwent standardized pre-surgical staging, treatments and regular follow-up visits. All tumours were evaluated, classified and graded according to published guidelines. Time to primary metastasis was the main endpoint in this study. Two bio-scoring systems were developed: The multivariate scoring (MVS) was based on traditional statistical analysis where only factors significant in the multivariate analysis (tumour size and grade) were kept for the final model. The refined flexible scoring (RFS) system was based on results from subgroup analysis, which guided the development of a flexible system. Progressive worsening prognosis was observed with increasing bio-scores in both systems. MVS: Median primary metastasis-free survival (TTM1 days) was not reached in dogs with bio-scores 0 to 5, 10, 15 and 648, 149, 317, in MVS groups 25, 30, 40, respectively. Similarly, TTM1 was not reached in dogs with RFS 0, 1, 2 and 374, 407 and 149, in dogs with bio-scores 3, 4, 5, respectively. However, a more distinct separation between dogs with high risk vs low risk for metastasis was observed with RFS, suggesting superior overall prognostication regarding the risk for metastasis.

Neuropathology of Spontaneous Hypertensive Encephalopathy in Cats.

Pathologic features of 12 cats with naturally acquired systemic hypertension and concomitant hypertensive encephalopathy were analyzed. All cats demonstrated acute onset of signs localized to the forebrain and/or brainstem, including stupor, coma, and seizures. All cats had systemic hypertension, ranging from 160 to 300 mm Hg. Gross lesions were identified in 4 of 12 cases, including caudal herniation of the cerebrum and cerebellum, sometimes with compression of the rostral colliculus and medulla. Histologically, all cases featured bilaterally symmetrical edema of the cerebral white matter. Associated vascular lesions, especially arteriolar hyalinosis, were also observed. Concurrent lesions were chronic tubulointerstitial nephritis (11/12 cases), adenomatous hyperplasia of the thyroid gland (4 cases), hypertensive choroidal arteriopathy (6 cases), and left ventricular hypertrophy (5 cases). This study demonstrates that the typical histologic manifestation of spontaneous hypertensive encephalopathy in cats is bilaterally symmetrical edema of the subcortical cerebral white matter.