Claire M. Cannon

Evaluation of a combination chemotherapy protocol including lomustine and doxorubicin in canine histiocytic sarcoma

OBJECTIVES To describe a chemotherapy protocol combining lomustine and doxorubicin in canine histiocytic sarcoma, including outcomes and toxicity. MATERIALS AND METHODS Retrospective review of case records for dogs with histiocytic sarcoma treated with lomustine and doxorubicin (± cyclophosphamide) alternating every 2 weeks. Data collected included signalment, clinical signs, clinicopathological abnormalities, extent of disease, response, toxicity, time to tumour progression and survival time. RESULTS Of 17 dogs, 15 had disseminated or metastatic disease. The median number of chemotherapy cycles (one dose of each drug) received was three; most dogs discontinued therapy due to progressive disease. Dose reductions or delays occurred in 18% of cycles. The overall response rate was 58%, with a median time to tumour progression of 185 (range, 59 to 268) days for responders. The overall median survival time was 185 (18 to 402) days. No significant prognostic factors were identified. CLINICAL SIGNIFICANCE The protocol appeared well-tolerated, had some efficacy against canine histiocytic sarcoma in the study population and could be considered as an alternative to single-agent protocols; prospective comparison may be warranted.

Canine osteosarcoma cells exhibit resistance to aurora kinase inhibitors

We evaluated the effect of Aurora kinase inhibitors AZD1152 and VX680 on canine osteosarcoma cells. Cytotoxicity was seen in all four cell lines; however, half-maximal inhibitory concentrations were significantly higher than in human leukaemia and canine lymphoma cells. AZD1152 reduced Aurora kinase B phosphorylation, indicating resistance was not because of failure of target recognition. Efflux mediated by ABCB1 and ABCG2 transporters is one known mechanism of resistance against these drugs and verapamil enhanced AZD1152-induced apoptosis; however, these transporters were only expressed by a small percentage of cells in each line and the effects of verapamil were modest, suggesting other mechanisms contribute to resistance. Our results indicate that canine osteosarcoma cells are resistant to Aurora kinase inhibitors and suggest that these compounds are unlikely to be useful as single agents for this disease. Further investigation of these resistance mechanisms and the potential utility of Aurora kinase inhibitors in multi-agent protocols is warranted.

Clinicopathologic features of lingual canine T-zone lymphoma

Canine T-zone lymphoma (TZL) is a subtype of T-cell lymphoma characterized by unique histologic pattern and cytomorphology, immunophenotypic loss of CD45 expression, and an indolent clinical behaviour. Dogs with TZL typically present with 1 or more enlarged lymph nodes and/or lymphocytosis. We describe a novel extranodal presentation of TZL involving the tongue. Twelve dogs with tongue masses were diagnosed with lingual TZL based on a variable combination of immunophenotyping via flow cytometry, cytology, histopathology, immunohistochemistry and/or PCR for antigen receptor rearrangement (PARR) assay. Eleven dogs exhibited concurrent lymphocytosis and/or lymph node enlargement. Three cases were initially diagnosed as plasma cell tumours based on histology alone, thereby revealing a potential diagnostic challenge. Seven dogs achieved clinical remission and 4 achieved stable disease following variable treatment, consistent with the indolent nature of typical TZL involving the lymph nodes and peripheral blood. In 1 case the TZL resulted in progressive disease and failure to respond to treatment. In this case, the TZL exhibited histologic features of a higher grade neoplasm. This case series highlights a unique presentation of TZL and identifies a new differential diagnosis for lingual neoplasia. In this study, we characterize the clinical presentation, diagnostic features and patient outcomes of 12 dogs with lingual TZL.

CK2 Molecular Targeting—Tumor Cell-Specific Delivery of RNAi in Various Models of Cancer

Protein kinase CK2 demonstrates increased protein expression relative to non-transformed cells in the majority of cancers that have been examined. The elevated levels of CK2 are involved in promoting not only continued proliferation of cancer cells but also their resistance to cell death; thus, CK2 has emerged as a plausible target for cancer therapy. Our focus has been to target CK2 catalytic subunits at the molecular level using RNA interference (RNAi) strategies to achieve their downregulation. The delivery of oligonucleotide therapeutic agents warrants that they are protected and are delivered specifically to cancer cells. The latter is particularly important since CK2 is a ubiquitous signal that is essential for survival. To achieve these goals, we have developed a nanocapsule that has the properties of delivering an anti-CK2 RNAi therapeutic cargo, in a protected manner, specifically to cancer cells. Tenfibgen (TBG) is used as the ligand to target tenascin-C receptors, which are elevated in cancer cells. This strategy is effective for inhibiting growth and inducing death in several types of xenograft tumors, and the nanocapsule elicits no safety concerns in animals. Further investigation of this therapeutic approach for its translation is warranted.

Clinical Signs, Treatment, and Outcome in Cats with Myeloma-Related Disorder Receiving Systemic Therapy.

Myeloma-related disorder (MRD) is an uncommon disease in cats, for which there is no established standard of care. In this retrospective study, we evaluated presentation, response to treatment, and toxicity in cats with MRD receiving systemic treatment. Previously reported prognostic factors were evaluated for their impact on survival in cats receiving chemotherapy. Of fifteen cases identified, thirteen received melphalan or cyclophosphamide +/- corticosteroids as first-line therapy. Chlorambucil was commonly used as rescue therapy in cats with progressive disease, or in cases of chemotherapy-related toxicity with first line agents. Overall response rates were 71% and 83% for melphalan- and cyclophosphamide-treated cats, respectively. Discontinuation of melphalan due to toxicity was common. Survival times for cats initially treated with melphalan or cyclophosphamide were not significantly different (median 252 and 394 days, respectively), and no statistically significant prognostic factors were identified. This study suggests that the combination of cyclophosphamide and corticosteroids is well tolerated and may be considered as first-line therapy for cats with systemic MRD.

Low‐grade gastrointestinal lymphoma in dogs: 20 cases (2010 to 2016)

OBJECTIVES To report the clinical presentation, treatment and prognosis of dogs with low-grade gastrointestinal lymphoma. MATERIALS AND METHODS Cases were solicited from the American College of Veterinary Internal Medicine Oncology Diplomate listserv. Medical records of dogs with low-grade gastrointestinal lymphoma diagnosed via a combination of histology and immunohistochemistry with or without analysis of polymerase chain reaction for antigen receptor rearrangement were included. Signalment, clinical signs, diagnostic test results, chemotherapy protocol, response to treatment, date of first progression, rescue therapies and date and cause of death or last follow-up visit were collected. RESULTS Twenty cases were included. Males and small breed dogs were over-represented. Frequent clinical signs included weight loss, vomiting and diarrhoea. Most lymphomas were T-cell phenotype (95%), and epitheliotropism was commonly described (60%). Immunohistochemistry, polymerase chain reaction for antigen receptor rearrangement or both were frequently required for definitive diagnosis. Two dogs had resection of an intestinal mass, and all dogs were treated with chemotherapy; chlorambucil and prednisone were most commonly prescribed. Overall response rate was 70%, and median survival time was 424 days (95% confidence interval: 105 to 1206 days). CLINICAL SIGNIFICANCE Low-grade gastrointestinal lymphoma appears to be a rare condition in dogs, and treatment with chemotherapy results in a high response rate and favourable survival times. Further study is needed to determine its prevalence in dogs with chronic enteropathies.

Prior joint disease is associated with increased risk of periarticular histiocytic sarcoma in dogs

Periarticular histiocytic sarcoma (PAHS) is the most common synovial tumour in dogs and is characterized by aggressive local disease with a high rate of distant metastasis. Previously, an association between PAHS and prior joint disease has been demonstrated in the Bernese Mountain Dog breed and suggested in the Rottweiler. We hypothesized that this association would be present in other breeds and investigated this via a retrospective, case-controlled analysis. Cases were dogs diagnosed with PAHS of the stifle or elbow. Controls were age, breed and sex-matched dogs without a diagnosis of histiocytic sarcoma. Diagnosis of prior joint disease was determined based on review of medical records and direct veterinarian and owner communications. Data were evaluated using logistic regression, 2-sampled t tests, and chi-squared analysis. Our study population consisted of 28 cases and 46 controls, including Flat-Coated, Golden and Labrador Retrievers, Rottweilers, English Bulldogs, Shih Tzus, Australian Shepherds, Staffordshire Terriers and mixed breed dogs. Dogs with PAHS were more likely to have prior joint disease in the tumour-affected joint compared with the control population (odds ratio [OR] = 13.42, P < .0001, 95% confidence interval [CI] = 4.33-48.63). A total of 88.2% of dogs with stifle PAHS had prior joint disease in their tumour-affected joint, most commonly cranial cruciate ligament rupture. This study confirms that the previously noted association between prior joint disease and PAHS in Bernese Mountain Dogs also applies to other breeds. Additional studies are needed to further investigate for a causal relationship.