Safety evaluation of combination carboplatin and toceranib phosphate (Palladia) in tumour-bearing dogs: A phase I dose finding study.

Combining conventional cytotoxic maximum tolerated dose (MTD) chemotherapy with low-dose metronomic and/or anti-angiogenic agents is a exciting area of oncologic research. The objective of this study was to establish the MTD, safety and adverse event (AE) profile of 1 such drug combination. This prospective phase I dose-finding clinical trial assumed an open-label 3 + 3 cohort design. Client-owned dogs with 1 or more cytologically and/or histologically confirmed and macroscopically measurable, naive or recurrent, malignant tumours, were enrolled. No preference for tumour histology, grade or stage was expressed. Toceranib was administered at a dose of 2.75 mg kg-1 by mouth (PO) every other day (EOD), and carboplatin administered intravenously (IV) every 21 days at a starting dose of 200 mg m-2 . A total of 25% dose escalation was proposed for carboplatin, to a maximum of 300 mg m-2 . AEs were graded according to the Veterinary Cooperative Oncology Group's common terminology criteria for AEs (VCOG-CTCAE). Grade 3 haematologic or gastrointestinal AEs were nominated dose-limiting. Response to therapy was evaluated according to the VCOG's revised RECIST criteria. Eleven dogs were enrolled. Tumour histologies included sinonasal carcinoma, osteosarcoma, thyroid carcinoma, melanoma and apocrine gland anal sac adenocarcinoma. MTDs of carboplatin and toceranib were identified as 200 mg m-2 IV every 21 days and approximately 2.75 mg kg-1 PO EOD, respectively. The dose-limiting toxicity was neutropenia. Two dogs experienced a partial response, and 6 maintained stable disease. Combination carboplatin and toceranib chemotherapy was well-tolerated. Clinical benefit was observed in most cases. This protocol warrants further investigation in phase II/III trials.

Safety evaluation of combination doxorubicin and toceranib phosphate (Palladia®) in tumour bearing dogs: a phase I dose-finding study.

Combination chemotherapy holds promise for improving outcomes in malignancy when compared with single-agent approaches. Care must be taken to avoid overlapping toxicity and to utilize agents with differing mechanisms of action. A phase I dose-finding trial was performed to determine the maximally tolerated dose (MTD) of a concurrent toceranib and doxorubicin (DOX) combination protocol where toceranib dose was maintained at or near 2.75 mg kg-1 by mouth every other day (PO EOD) while escalating DOX dosage. The dose-limiting toxicity was found to be neutropenia and the MTD of the combination was determined to be 25 mg m-2 of DOX q 21 days given concurrently with toceranib 2.75 mg kg-1 PO EOD. This combination was well tolerated with no excessive gastrointestinal toxicity nor novel adverse events (AEs) noted. Anti-tumour activity was observed in the majority of cases. This combination warrants further investigation in the context of phase II/III clinical trials to characterize efficacy and long-term AE profiles.

Development of an autologous canine cancer vaccine system for resectable malignant tumors in dogs.

While conventional therapies exist for canine cancer, immunotherapies need to be further explored and applied to the canine setting. We have developed an autologous cancer vaccine (K9-ACV), which is available for all dogs with resectable disease. K9-ACV was evaluated for safety and immunogenicity for a variety of cancer types in a cohort of companion dogs under veterinary care. The autologous vaccine was prepared by enzymatic digestion of solid tumor biopsies. The resultant single cell suspensions were then UV-irradiated resulting in immunogenic cell death of the tumor cells. Following sterility and endotoxin testing, the tumor cells were admixed with CpG ODN adjuvant and shipped to the participating veterinary clinics. The treating veterinarians then vaccinated each patient with three intradermal injections (10 million cells per dose) at 30-day intervals (one prime and two boost injections). In a cohort of 20 dogs completing the study, 17 dogs (85%) developed an augmented IgG response to autologous tumor antigens as demonstrated using western blot analysis of pre- and post-peripheral blood samples. We also report several dogs have lived beyond expected survival time based on previously published data. In summary, K9-ACV is an additional option to be considered for the treatment of dogs with resectable cancer.

Evaluation of adjuvant carboplatin chemotherapy in the management of surgically excised anal sac apocrine gland adenocarcinoma in dogs.

There is no widely accepted standard of care for canine anal sac apocrine gland adenocarcinoma (ASAGAC). Surgery alone is inadequate in many cases, but the benefit of adjuvant chemotherapy is not well established. The primary objective of this retrospective study was to evaluate the role of carboplatin chemotherapy in the post-operative management of ASAGAC. Seventy-four dogs with naturally occurring ASAGAC underwent surgery. Forty-four dogs received adjuvant carboplatin and 30 did not. Median overall survival (OS) was 703 days. Median time to progression (TTP) was 384 days. Only primary tumour size and lymph node metastasis at diagnosis significantly impacted the outcome. Differences in OS and TTP, between the dogs that received adjuvant carboplatin and those that did not, failed to reach statistical significance. Treatment of progressive disease, whilst not limited to chemotherapy, significantly prolonged the survival. This study shows that adjuvant carboplatin chemotherapy is well tolerated and may have a role in the management of dogs with ASAGAC.

Venous Side Branch Ligation as a First Step Treatment for Haemodialysis Access Induced Hand Ischaemia: Effects on Access Flow Volume and Digital Perfusion.

OBJECTIVE: Haemodialysis access induced distal ischemia (HAIDI) induced by an autogenous arteriovenous fistula (AVF) is caused by loss of blood pressure somewhere along the arterial blood supply of the arm. In some patients, side branches of the access' venous outflow tract may contribute to this blood pressure loss. Beneficial effects of side branch ligation (SBL) as a first step approach to ischemic symptoms have been reported. However, effects on access flow and AVF function after prolonged follow up are unknown. MATERIALS AND METHODS: Prior to SBL, HAIDI patients with a brachial artery based AVF were studied using a questionnaire quantifying hand ischemia, digital brachial index (DBI, finger plethysmography), and Duplex analysis. Access flow volume, patency rates, hand perfusion, and complications were determined during a 12 month observation period following SBL. RESULTS: In 9 years, SBLs were performed in 20 haemodialysis patients, either as a single operative procedure (n = 10) or supplemented (n = 10) with additional surgical techniques during the same procedure (banding, n = 5; basilic vein transposition, n = 4; DRIL, n = 1). Follow up data after 12 months were available in 18 patients. One patient with progressive hand ischemia required access ligation 3 months after SBL. Hand ischemia was attenuated or abolished in the remaining 17 patients (94% clinical success rate). DBI improved from 0.51 ± 0.05 (pre-operative) to 0.68 ± 0.04 (immediate post-operative) and 0.83 ± 0.07 (at 1 year follow up). One year primary, assisted primary, and secondary patency rates were 67% (12/18), 83% (15/18), and 94% (17/18), respectively, while mean access flows remained acceptable at 710 ± 70 mL/min. CONCLUSIONS: Ligation of non-functional venous side branches of an autogenous brachial artery AVF causing hand ischemia leads to prolonged attenuation of hand ischemia whereas access flow volumes are maintained after 1 year of follow up. Side branch ligation must be considered prior to embarking on more invasive surgery for HAIDI.

Hepatic myelolipoma incarcerated in a peritoneopericardial diaphragmatic hernia in a cat.

Hepatic myelolipoma incarcerated in a peritoneopericardial diaphragmatic hernia was diagnosed in an 11-year-old, desexed female Persian cat. The cat was initially referred for investigation of tachypnoea and dyspnoea. Peritoneopericardial diaphragmatic hernia is a common incidental finding in cats and is usually asymptomatic. Myelolipoma is an extremely rare benign tumour, composed of extramedullary haematopoietic cells and adipose tissue. Myelolipomas are hypothesised to result from metaplastic alteration, rather than a neoplastic process, although this theory cannot be substantiated. The present case is only the fourth report of such an unusual occurrence in cats and displays significant differences to previous reports. Hepatic entrapment and burgeoning of the mass within the pericardial sac resulted in cardiac tamponade and overt signs of right-sided cardiac failure. Surgical intervention was successful and despite concerns regarding the cat's clinical presentation and the gross appearance of the lesion(s), a good long-term outcome is anticipated.