Treatment of multiple synchronous canine mast cell tumours using intratumoural tigilanol tiglate.

Mast cell tumours (MCTs) are common canine skin neoplasia. While they generally occur as single tumours, multiple synchronous MCTs (msMCTs) of de novo/non-metastatic origin are reported in a proportion of the patient population. Where there is no evidence of metastasis or lymphatic spread, MCTs are effectively controlled by surgery and other local therapies. However, treatment of de novo msMCTs can be more challenging, especially when they occur in surgically difficult locations. Here, we report the use of tigilanol tiglate, a novel small molecule registered as a veterinary pharmaceutical for the local treatment of non-metastatic MCTs, in the treatment of patients with msMCTs presenting at three Australian specialist referral centres. We also present a meta-analysis of the literature to provide a better understanding of the prevalence of canine msMCTs. Notably, nine patients with a total of 32 MCTs were treated during the study. A complete response was recorded in 26 (81%) of the individual MCTs on Day 28 after a single tigilanol tiglate injection. Of the 6 initially non-responsive MCTs, one achieved a complete response after a further tigilanol tiglate treatment. A complete response was reported at 6 months in all 22 of the tumours that were evaluable and that had recorded a complete response at Day 84. For the literature meta-analysis, 22 studies were found with prevalence estimates of msMCTs ranging from 3 to 40%; when combined, these studies yielded 3,745 patients with a prevalence of 13% (95% CI 10; 16). Overall, the results demonstrate the utility of intratumoural tigilanol tiglate as an option for the treatment of multiple MCTs where multiple surgical resections would have been required.

Procarbazine, prednisolone and cyclophosphamide oral combination chemotherapy protocol for canine lymphoma.

Orally administered daily chemotherapy offers a novel treatment approach for canine lymphoma in a population of dogs that have failed or not tolerated maximum tolerable dose chemotherapy. A multidrug oral chemotherapy protocol was designed and implemented for the treatment of 50 dogs with multicentric lymphoma with minimal side effects. The protocol consisted of oral procarbazine, prednisolone and cyclophosphamide (PPC) administered daily. Efficacy and toxicity were evaluated by clinical and laboratory evaluation. An overall response rate of 70% was achieved, with 24% and 46% of dogs having a partial and complete response, respectively, to treatment with the PPC protocol. Response to the PPC protocol (complete or partial) and age were the only factors identified as prognostic for time from initiation of the PPC chemotherapy until death. Overall, the protocol was very well tolerated with only one dog requiring protocol discontinuation due to grade 4 thrombocytopenia. Eight dogs recorded gastrointestinal toxicities, seven grade I and one grade II toxicity. These findings demonstrate that the administration of a continuous oral combination chemotherapy can provide comparable survival times in the rescue setting in dogs with multicentric lymphoma with minimal side effects.

Evaluation of a modified proportional margin approach for complete surgical excision of canine cutaneous mast cell tumours and its association with clinical outcome.

Canine cutaneous mast cell tumours (MCTs) represent a common neoplasm in veterinary practice. Several reported techniques are available to guide surgical excision. Our study examined one hundred cutaneous MCTs that were excised surgically using a modified proportional margin approach. A 2 cm lateral margin upper limit was applied for any tumour diameter that exceeded this size with a deep surgical margin of one fascial plane applied. A retrospective, cross-sectional study with follow-up was used to determine the clinical utility of this excision technique. Associations between explanatory variables of tumour size and grade were compared with outcomes of complete excision and size of histologic tumour-free margins (HTFM) using the appropriate Pearson's χ2 and Fisher's exact tests. Follow-up data evaluated tumour recurrence and patient survival. Ninety-five percent of MCTs (95/100) were completely excised. No significant association in the achievement of complete excision between low- and high-grade MCTs (P = .48) was noted. Tumour size was not associated with the rate of complete excision (P = .06). Tumour grade and size did not influence the size of the HTFM (P = .94 and P = .14, respectively). Overall, a recurrence rate of 3% (3/100 tumours) and de novo MCT development rate of 7.7% (5/65 dogs) was noted, with median follow-up period of 593 days (range 180-1460 days). Post-operative metastases were seen in 4.6% of dogs (3/65). Therefore, a modified proportional margin approach with 2 cm lateral margin upper limit is a suitable technique to guide surgical excision of canine cutaneous MCTs.

Auranofin improves overall survival when combined with standard of care in a pilot study involving dogs with osteosarcoma.

Osteosarcoma is the most common paediatric primary bone malignancy. The major cause of death in osteosarcoma is drug-resistant pulmonary metastasis. Previous studies have shown that thioredoxin reductase 2 is a driver of metastasis in osteosarcoma and can be inhibited by auranofin (AF). Moreover, studies have shown that AF significantly reduces pulmonary metastases in xenotransplant models. Here, we describe a phase I/II study of AF in canine osteosarcoma, a well-recognized spontaneous model of human osteosarcoma. We performed a single-arm multicentre pilot study of AF in combination with standard of care (SOC) (amputation + carboplatin). We recruited 40 dogs to the trial and used a historical SOC-only control group (n = 26). Dogs >15 kg received 9 mg AF q3d PO and dogs <15 kg received 6 mg q3d. Follow-up occurred over at least a 3-year period. Auranofin plus SOC improved overall survival (OS) (P = .036) in all dogs treated. The improved outcome was attributable entirely to improved OS in male dogs (P = .009). At the time of writing, 10 dogs (25%) survive without measurable disease in the treatment group with survival times ranging between 806 and 1525 days. Our study shows that AF improves OS in male dogs when combined with SOC. Our findings have translational relevance for the management of canine and human osteosarcoma. Our data justify a larger multicentre phase 2 trial in dogs and a phase I/II trial in human patients with refractory disease at the time of initial surgery.

Primary Hepatic Neuroendocrine Carcinoma Treated with Doxorubicin and Cyclophosphamide in a Dog.

A 7 yr, 6 mo old male neutered Australian cattle dog cross presented to a referral hospital with a large abdominal mass. An abdominal ultrasound revealed multifocal lesions throughout the liver, which were suspicious for intrahepatic metastasis, with no evidence of extrahepatic metastatic disease. Cytology indicated neoplasia of epithelial origin, with neuroendocrine neoplasia the primary suspicion. The patient was started on a maximally tolerated chemotherapy protocol of doxorubicin and metronomic cyclophosphamide. Stable disease was found on repeat abdominal ultrasounds, and the patient tolerated the protocol well. On completion of five doxorubicin doses, the dog was continued on metronomic cyclophosphamide and meloxicam. Progressive hepatic disease was found at 10 mo. The patient was euthanized 15.5 mo (465 days) after commencing treatment. Histopathology and immunohistochemistry (synaptophysin) performed on liver collected postmortem indicated (primary) hepatic neuroendocrine carcinoma. Primary hepatic neuroendocrine carcinomas are rare in dogs, and there is no standard of care for treatment. To the authors' knowledge, this is the first report of a primary hepatic neuroendocrine carcinoma treated with high-dose doxorubicin and metronomic cyclophosphamide.

Patient and tumour factors influencing canine mast cell tumour histological grade and mitotic index.

The aim of this study was to identify patient and tumour factors most frequently associated with high histological grades of canine mast cell tumours (MCTs). Search criteria in a shared database of multiple Animal Referral Hospital locations within Australia generated 400 canine MCTs in 286 patients. Patient and tumour data were extrapolated and the association between a tumour being histologically high grade and patient and tumour factors, including: patient breed, patient gender and neuter status, patient age at MCT excision, tumour location and tumour size was assessed using univariate analysis. The study consisted of 90 (21.9%) tumours meeting histological high-grade criteria. Shar peis were the most likely breed to have high grade MCTs, whereas the Pug and the Golden Retriever were the least likely breeds to develop high-grade MCTs. No significant difference in risks could be established between the age at which the tumour was excised, or the gender and neuter status of patients. MCTs of the inguinal region were the most likely single location to be high grade. Tumour size did not influence the likelihood of a tumour being high grade or low grade. The results of this study suggest that patient and tumour factors may play a role in the histological grades of canine MCTs.

Combination vinblastine, prednisolone and toceranib phosphate for treatment of grade II and III mast cell tumours in dogs.

This retrospective study evaluates the progression-free interval and survival outcomes of 40 canine (Canis familiaris) patients with Patnaik grade II and III mast cell tumours treated with combination vinblastine, prednisolone and toceranib phosphate from 2011 to 2015. Patients were subdivided into three groups; patients who received neoadjuvant therapy for poorly operable lesions, patients who received adjuvant therapy following surgical resection and patients being palliated for gross metastatic disease. Median survival time (MST) for the neoadjuvant group was not reached. Median survival time for the remaining groups was 893 days and 218 days, respectively. This combination demonstrated response in 90% (26/29) patients with measurable disease. The predominant side effects related to this chemotherapy combination were gastrointestinal in origin. Further prospective studies are required to further validate the efficacy of this treatment protocol.

Complications and outcomes following rectal pull-through surgery in dogs with rectal masses: 74 cases (2000-2013).

OBJECTIVE: To evaluate the incidence of and factors associated with complications following rectal pull-through (RPT) surgery and the outcome for dogs with rectal tumors. DESIGN: Retrospective case series. ANIMALS: 74 dogs with rectal masses. PROCEDURES: Information regarding signalment, history, diagnostic testing, type of rectal disease, surgical details, and postoperative complications, treatments, and outcomes was obtained from medical records and follow-up communications. Survival times were calculated. Descriptive statistics were generated. Regression analyses were used to evaluate the effect of various variables on the development of postsurgical complications and survival time. RESULTS: 58 (78.4%) dogs developed postsurgical complications, the most common of which was fecal incontinence with 42 (56.8%) dogs affected, of which 23 (54.8%) developed permanent incontinence. Other complications included diarrhea (n = 32), tenesmus (23), stricture formation (16), rectal bleeding (8), constipation (7), dehiscence (6), and infection (4). The rectal tumor recurred in 10 dogs. The median survival time was 1,150 days for all dogs and 726 days for dogs with malignant tumors. The 2 most common rectal masses were rectal carcinoma and rectal carcinoma in situ, and the dogs with these tumors had median survival times of 696 and 1,006 days, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Dogs with rectal diseases that underwent RPT surgery had a high incidence of complications; however, those dogs had good local tumor control and survival times. The risk and impact of postsurgical complications on the quality of life and oncological outcomes should be discussed with owners before RPT surgery is performed in dogs with rectal masses.

Squamous cell carcinoma of the nasal planum in cats and dogs.

The purpose of this article is to review the therapeutic options available for the treatment of squamous cell carcinoma of the nasal planum in cats and dogs. The techniques of complete and partial nasal planum resection in the cat are described in detail. Surgical treatment offers the greatest chance of cure, although several options are available for early, less invasive lesions.

Combined dorsolateral and intraoral approach for the resection of tumors of the maxilla in the dog.

This paper describes in detail a combined dorsal and intraoral approach for maxillectomy for tumors involving tissues more caudal to the third premolar. The only intraoperative complication was that of blood loss, with six out of 20 dogs requiring a single unit of blood. Histopathologically clean margins were obtained in 14 of the 20 cases, with a recurrence rate of 50% in these dogs and a median time to recurrence of 24 months. This represents an improvement in outcome over previously reported studies, and the authors postulate this is due to the better exposure and access to the area afforded by the combined approach over the standard intraoral approach.