Novel genomic prognostic biomarkers for dogs with cancer.

BACKGROUND: Growing evidence from dogs and humans supports the abundance of mutation-based biomarkers in tumors of dogs. Increasing the use of clinical genomic diagnostic testing now provides another powerful data source for biomarker discovery. HYPOTHESIS: Analyzed clinical outcomes in dogs with cancer profiled using SearchLight DNA, a cancer gene panel for dogs, to identify mutations with prognostic value. ANIMALS: A total of 127 cases of cancer in dogs were analyzed using SearchLight DNA and for which clinical outcome information was available. METHODS: Clinical data points were collected by medical record review. Variables including mutated genes, mutations, signalment, and treatment were fitted using Cox proportional hazard models to identify factors associated with progression-free survival (PFS). The log-rank test was used to compare PFS between patients receiving and not receiving targeted treatment before first progression. RESULTS: Combined genomic and outcomes analysis identified 336 unique mutations in 89 genes across 26 cancer types. Mutations in 6 genes (CCND1, CCND3, SMARCB1, FANCG, CDKN2A/B, and MSH6) were significantly associated with shorter PFS. Dogs that received targeted treatment before first progression (n = 45) experienced significantly longer PFS compared with those that did not (n = 82, P = .01). This significance held true for 29 dogs that received genomically informed targeted treatment compared with those that did not (P = .05). CONCLUSION AND CLINICAL IMPORTANCE: We identified novel mutations with prognostic value and demonstrate the benefit of targeted treatment across multiple cancer types. These results provide clinical evidence of the potential for genomics and precision medicine in dogs with cancer.

Diagnosis and Management of an Oronasal Fistula Secondary to Nasal Transmissible Venereal Tumor in a Dog.

Canine transmissible venereal tumor (CTVT) is a contagious tumor commonly seen in populations of sexually intact dogs that have close contact with each other. CTVT is one of only 3 known naturally transmissible, contagious tumors in which the mutated tumor cell is thought to have originated in an individual canid about 11000 years ago. Clinical history, signalment, cytological and histologic evaluation are typically sufficient for reaching a diagnosis, although immunohistochemistry(IHC) may be necessary for unique presentations of this neoplasm. This case report describes the diagnosis of an oronasal CTVT using histopathology and IHC, followed by treatment of the tumor with chemotherapy and surgical correction of a defect caused by the tumor.

Apocrine gland anal sac adenocarcinoma in cats: 30 cases (1994-2015).

OBJECTIVE To describe the signalment, clinical signs, biological behavior, and outcome for cats with apocrine gland anal sac adenocarcinoma (AGASACA) that underwent surgical excision. DESIGN Retrospective case series. ANIMALS 30 client-owned cats. PROCEDURES Databases of 13 Veterinary Society of Surgical Oncology member-affiliated institutions were searched for records of cats with a histologic diagnosis of AGASACA that underwent tumor excision. For each cat, information regarding signalment, clinical signs, diagnostic test results, treatment, and outcome was extracted from the medical record. The Kaplan-Meier method was used to determine median time to local recurrence (TLR), disease-free interval (DFI), and survival time. Cox regression was used to identify factors associated with TLR, DFI, and survival time. RESULTS Perineal ulceration or discharge was the most common clinical sign in affected cats. Eleven cats developed local recurrence at a median of 96 days after AGASACA excision. Incomplete tumor margins and a high nuclear pleomorphic score were risk factors for local recurrence. Nuclear pleomorphic score was negatively associated with DFI. Local recurrence and a high nuclear pleomorphic score were risk factors for death. Median DFI and survival time were 234 and 260 days, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that, in cats, perineal ulceration or discharge should raise suspicion of AGASACA and prompt rectal and anal sac examinations. Local recurrence was the most common life-limiting event in cats that underwent surgery for treatment of AGASACA, suggesting that wide margins should be obtained whenever possible during AGASACA excision. Efficacy of chemotherapy and radiation therapy for treatment of cats with AGASACA requires further investigation. (J Am Vet Med Assoc 2019;254:716-722).

Primary pulmonary histiocytic sarcoma in dogs: A retrospective analysis of 37 cases (2000-2015).

Primary pulmonary histiocytic sarcoma (PHS) has been reported, but is not well characterized. The aim of this retrospective study was to describe clinical characteristics, characterize prognostic factors and report the outcome of a larger group of dogs with primary PHS. Medical records of dogs diagnosed with primary PHS at 11 institutions were retrospectively reviewed. Thirty-seven dogs were included; 13 received CCNU-based chemotherapy alone, 18 received surgery and adjuvant CCNU-based chemotherapy, 3 received medical management alone and 3 dogs received surgery alone. The overall median progression free survival (PFS) and the median survival (overall survival [OS]) were 197 and 237 days, respectively. Measurable responses were noted in dogs receiving only chemotherapy; however, responses were not durable with PFS (91 days) and OS times (131 days) shorter than overall medians. Dogs that received surgery and chemotherapy had significantly prolonged PFS (276 days, P = 0.001) and OS (374 days, P = 0.001), compared with dogs not receiving surgery. As only three dogs undergoing surgery did not receive chemotherapy, it is not possible to determine the contribution of chemotherapy as an adjuvant to surgery. Dogs without evidence of intra-thoracic metastatic disease were much more likely to undergo surgery (odds ratio = 7.04; P = 0.018). While the presence of metastasis or clinical signs at diagnosis negatively impacted PFS, only the former negatively impacted OS. These data imply that dogs presenting with PHS amenable to surgery (ie, no clinical evidence of metastasis) benefit from surgical intervention; however, the lack of a comparable surgery alone group precludes assessment of the efficacy of post-surgical adjuvant chemotherapy.

Post-surgical outcome and prognostic factors in canine malignant melanomas of the haired skin: 87 cases (2003-2015).

The medical records of 87 dogs treated with surgery for cutaneous malignant melanoma (CMM) of the haired skin were retrospectively reviewed for overall survival time (OST), progression-free survival time (PFS), and prognostic factors. The post-surgery median PFS and median OST were 1282 days and 1363 days, respectively. The post-surgery metastatic rate was 21.8% with a local recurrence rate of 8%. Increasing mitotic index (MI) was predictive of a significantly decreased OST and PFS on multivariable analysis [hazard ratio (HR): 1.05, 95% confidence interval (CI): 1.02 to 1.07 and HR: 1.04, 95% CI: 1.02 to 1.06, respectively]. Increasing age was likewise predictive of a significantly decreased OST and PFS on multivariable analysis (HR: 1.39, 95% CI: 1.17 to 1.65 and HR: 1.33, 95% CI: 1.14 to 1.54, respectively). These results confirm clinical impressions that long survival times are likely in dogs diagnosed with malignant melanoma of the haired skin when treated with surgery alone.

Résultat post-chirurgical et facteurs de pronostic pour les mélanomes malins canins de la peau poilue : 87 cas (2003­2015). Les dossiers médicaux de 87 chiens traités à l'aide d'une chirurgie pour le mélanome malin cutané (MMC) de la peau poilue ont été évalués rétrospectivement pour le temps de survie global (TSG), le temps de survie sans progression (TSSP) et les facteurs de pronostic. Le TSSP médian après la chirurgie et le TSG médian étaient de 1282 jours et de 1363 jours, respectivement. Le taux métastasique après la chirurgie était de 21,8 % avec un taux de récurrence local de 8 %. L'augmentation de l'indice mitotique (IM) était prédictive d'un TSG et d'un TSSP réduits à l'analyse multivariable (ratio de risque [RR] : 1,05, intervalle de confiance [IC] de 95 % : 1,02 à 1,07 et RR : 1,04, IC de 95 % : 1,02 à 1,06, respectivement). La progression de l'âge était aussi prédictive d'une réduction importante du TSG et du TSSP à l'analyse multivariable (RR : 1,39, IC de 95 % : 1,17 à 1,65 et RR : 1,33, IC de 95 % : 1,14 à 1,54, respectivement). Ces résultats confirment les impressions cliniques que des longs délais de survie sont probables chez les chiens diagnostiqués avec le mélanome malin de la peau poilue lorsqu'ils sont uniquement traités à l'aide d'une chirurgie.(Traduit par Isabelle Vallières).

Primary appendicular hemangiosarcoma and telangiectatic osteosarcoma in 70 dogs: A Veterinary Society of Surgical Oncology retrospective study.

OBJECTIVE: To define and compare clinical characteristics of canine primary appendicular hemangiosarcoma (HSA) and telangiectatic osteosarcoma (tOSA), including signalment, presentation, response to treatment, and prognosis. STUDY DESIGN: Multi-institutional retrospective study. ANIMALS: Seventy dogs with primary appendicular HSA or tOSA. METHODS: Patient data were obtained from institutions' medical records. Immunohistochemistry was applied to archived tissues to establish tumor type. Patient characteristics, treatment responses, and outcomes were described and compared by tumor type. RESULTS: Forty-one HSA and 29 tOSA were identified. Dogs with HSA were more likely than dogs with tOSA to be male and have hind limb tumors; 78% of HSA occurred in hind limbs, particularly the tibia. Dogs with tOSA weighed a median of 9.9 kg (95% CI 4.6-15.3) more than dogs with HSA. Most dogs received antineoplastic treatment, predominantly amputation with or without adjuvant chemotherapy. Overall survival with local treatment and chemotherapy was 299 days (95% CI 123-750) for HSA and 213 days (95% CI 77-310) for tOSA. Younger age and more aggressive treatment were associated with longer survival in dogs with HSA but not tOSA. One-year survival rates did not differ between dogs with HSA (28%) and those with tOSA (7%). CONCLUSION: Distinct clinical features were identified between HSA and tOSA in this population. Both tumors were aggressive, with a high incidence of pulmonary metastases. However, local treatment combined with chemotherapy led to an average survival 7 months for tOSA and 10 months for HSA. CLINICAL SIGNIFICANCE: HSA should be considered as a differential in dogs with aggressive lytic bone lesions, particularly medium-sized dogs with tibial lesions. HSA has a unique clinical presentation but similar therapeutic response and outcome to OSA. Amputation and chemotherapy appear to prolong survival in some dogs with HSA and tOSA.

Avian Oncology: Diseases, Diagnostics, and Therapeutics.

Companion birds are increasingly living longer due to improved husbandry, nutrition, and veterinary care. As a consequence, a growing number of geriatric disease conditions are diagnosed and managed by veterinarians. Awareness of bird owners of diagnostic and treatment options for neoplastic diseases in humans and domestic animals has led to increasing demand to provide advanced diagnostic and treatment modalities for companion birds diagnosed with neoplasia. Treatment remains challenging in many companion birds due to the lack of information regarding prognosis and efficacy of antineoplastic treatments in these species. There is no established standard of care for most tumors in companion birds.

Paraganglioma, pituitary adenoma, and osteosarcoma in a dog.

An 11-year-old neutered male Alaskan Malamute mixed-breed dog was presented with a complaint of polyuria/polydipsia (PU/PD), weight loss, tachypnea, regurgitation, and a previous history of nontreated osteosarcoma of the right distal radius, diagnosed 21 months prior. On physical examination, an abdominal mass was palpated. The abdominal mass was aspirated and cytologically diagnosed as a neuroendocrine tumor, suspected to be a pheochromocytoma. Laboratory examination revealed a mild anemia and thrombocytopenia, markedly elevated ATP and ALP activities, and moderate hypercalcemia. A low-dose dexamethasone suppression test and endogenous adrenocorticotropic hormone (ACTH) concentration were compatible with pituitary hyperadrenocorticism. On urinalysis, proteinuria was noted as well as a high urine metanephrine/creatinine ratio, consistent with a diagnosis of pheochromocytoma. The dog was treated with supportive care and euthanized 6 months later due to decreasing quality of life. On necropsy, an extra-adrenal pheochromocytoma (paraganglioma) was diagnosed in the caudal abdomen, and a pituitary adenoma and an osteosarcoma of the right distal radius were confirmed.

Diagnosis and surgical treatment of a malignant trichoepithelioma of the ear canal in a pet rabbit (Oryctolagus cuniculus).

CASE DESCRIPTION: A 10-year-old spayed female Holland Lop-mix pet rabbit (Oryctolagus cuniculus) was evaluated because of purulent-hemorrhagic discharge from the right ear canal and a suspected mass within that ear canal. CLINICAL FINDINGS: Results of contrast-enhanced CT, video otoscopy, and histologic examination of endoscopic tissue biopsy samples indicated severe otitis media and externa and a benign trichoepithelioma of the right ear canal. TREATMENT AND OUTCOME: Total ear canal ablation and lateral bulla osteotomy were performed. Histologic examination of a surgical biopsy sample of the mass indicated malignant trichoepithelioma. Tumor recurrence was detected 22 weeks after surgery. The rabbit was euthanized 33 weeks after surgery because of the large size of the recurrent tumor and declining quality of life. Necropsy findings indicated a malignant trichoepithelioma with local and lymphatic invasion into the right mandibular lymph node. CLINICAL RELEVANCE: This was the first report of the clinical diagnosis, surgical treatment, and outcome for a domestic rabbit with a diagnosis of a malignant trichoepithelioma of the ear canal and associated otitis media and externa. Neoplasia should be included as a differential diagnosis for pet rabbits with otitis externa and media. Although such tumors are typically benign, trichoepitheliomas in rabbits can be malignant. Computed tomography and histologic examination of tissue samples were useful diagnostic techniques, but histologic examination of an endoscopic biopsy sample did not allow identification of malignant characteristics of the trichoepithelioma.

Clinical features, treatment options, and outcome in dogs with thymoma: 116 cases (1999-2010).

OBJECTIVE: To describe clinical signs, diagnostic findings, treatment, and outcome and determine factors associated with survival time for dogs with thymoma. DESIGN: Multi-institutional retrospective case series. ANIMALS: 116 dogs with thymoma. PROCEDURES: Medical records were searched for information regarding signalment, physical examination findings, results of laboratory testing and diagnostic imaging, medical and surgical treatment, and survival data. RESULTS: Of the 116 dogs with thymoma, 44 (38%) were Labrador Retrievers and Golden Retrievers. Twenty of 116 (17%) dogs had signs of myasthenia gravis (diagnosis was confirmed for 13 dogs). At the time of thymoma diagnosis, 40 (34%) dogs had hypercalcemia, 8 (7%) dogs had a concurrent immune-mediated disease, and 31 (27%) dogs had another tumor; 16 (14%) dogs developed a second nonthymic tumor at a later date. Tumor excision was performed for 84 dogs, after which 14 (17%) had tumor recurrence; prognosis was good for dogs undergoing a second surgery. Median survival time with and without surgical treatment was 635 and 76 days, respectively. Presence of another tumor at the time of thymoma diagnosis, lack of surgical excision, and higher pathological stage were significantly associated with shorter survival time. Hypercalcemia and presence of myasthenia gravis or megaesophagus at the time of thymoma diagnosis, histopathologic subtype of thymoma, or tumor development at a later date was not associated with survival time. CONCLUSIONS AND CLINICAL RELEVANCE: Dogs with thymoma, even those with a large tumor burden or a paraneoplastic syndrome, had a good prognosis following surgery. Surgical treatment, tumor stage, and the presence of a second tumor at diagnosis influenced survival time.

Assessment of GS-9219 in a pet dog model of non-Hodgkin's lymphoma.

PURPOSE: To assess, in dogs with naturally occurring non-Hodgkin's lymphoma, pharmacokinetics, safety, and activity of GS-9219, a prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyl) guanine (PMEG), which delivers PMEG and its phosphorylated metabolites to lymphoid cells with preferential cytotoxicity in cells with a high proliferation index such as lymphoid malignancies. EXPERIMENTAL DESIGN: To generate proof-of-concept, a phase I/II trial was conducted in pet dogs (n = 38) with naturally occurring non-Hodgkin's lymphoma using different dose schedules of GS-9219. A subset of dogs was further evaluated with 3'-deoxy-3'-(18)F-fluorothymidine positron emission tomography/computed tomography imaging before and after treatment. RESULTS: The prodrug had a short plasma half-life but yielded high and prolonged intracellular levels of the cytotoxic metabolite PMEG diphosphate in peripheral blood mononuclear cells in the absence of detectable plasma PMEG. Dose-limiting toxicities were generally manageable and reversible and included dermatopathy, neutropenia, and gastrointestinal signs. Antitumor responses were observed in 79% of dogs and occurred in previously untreated dogs and dogs with chemotherapy-refractory non-Hodgkin's lymphoma. The median remission durations observed compare favorably with other monotherapies in dogs with non-Hodgkin's lymphoma. High 3'-deoxy-3'-(18)F-fluorothymidine uptake noted in lymphoid tissues before treatment decreased significantly after treatment (P = 0.016). CONCLUSIONS: GS-9219 was generally well tolerated and showed significant activity against spontaneous non-Hodgkin's lymphoma as modeled in pet dogs and, as such, supports clinical evaluation in humans.