Cecilia Robat

Assessment of GS-9219 in a Pet Dog Model of Non-Hodgkin's Lymphoma

Purpose: To assess, in dogs with naturally occurring non-Hodgkins 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-Hodgkins lymphoma using different dose schedules of GS-9219. A subset of dogs was further evaluated with 3′-deoxy-3′-18F-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-Hodgkins lymphoma. The median remission durations observed compare favorably with other monotherapies in dogs with non-Hodgkins lymphoma. High 3′-deoxy-3′-18F-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-Hodgkins lymphoma as modeled in pet dogs and, as such, supports clinical evaluation in humans.

Safety evaluation of combination vinblastine and toceranib phosphate (Palladia®) in dogs: a phase I dose‐finding study

Combining drugs with known single-agent activity that lack overlapping dose-limiting toxicities (DLT) and exert antitumour activity through different mechanisms could improve clinical outcome. As toceranib and vinblastine meet these requisites, a phase I trial was performed in combination in dogs with mast cell tumours. The DLT for the simultaneous combination was neutropenia and the maximally tolerated dose was vinblastine (1.6 mg m(-2) every other week) concurrent with toceranib (3.25 mg kg(-1) PO, every other day). This represents greater than a 50% reduction in dose intensity for vinblastine (compared with single-agent use) and as such does not support this combination based on current drug combination paradigms. Although a strict adherence to dose paradigms speaks against the combination, evidence of significant activity (71% objective response) and enhanced myelosuppression suggest additive or synergistic activity. A prospective randomized evaluation comparing this combination with standard single-agent treatments would seem prudent to interrogate this potential.

Retrospective evaluation of doxorubicin-piroxicam combination for the treatment of transitional cell carcinoma in dogs.

OBJECTIVES To determine whether doxorubicin-piroxicam combination is safe and has activity against transitional cell carcinoma in dogs. METHODS Data was collected retrospectively from 34 dogs from two institutions over a 6-year period. Signalment, clinical presentation, treatment specifics, adverse events, response, progression-free survival and overall survival time were evaluated. RESULTS Dogs received doxorubicin every 3 weeks and daily piroxicam; 17 dogs (50%) had surgery. Clinical presentations were those typically reported for transitional cell carcinoma. Mean number of doses administered was 3·5. Of the 23 dogs with measurable disease, 14 (60·5%) had stable disease, 7 (30·5%) had progressive disease and 2 (9%) a partial response. Adverse events were generally manageable, and gastrointestinal in origin; one dog died of treatment-related complications. Overall median progression-free survival and overall survival were 103 and 168 days, respectively. Cytoreductive surgery did not result in prolongation of progression-free survival, but significantly prolonged overall survival. All dogs but one died as a result of disease progression. CLINICAL SIGNIFICANCE Doxorubicin-piroxicam combination therapy is well-tolerated in dogs with transitional cell carcinoma although progression-free survival, overall survival and biological response rates appear modest. Combination with surgery appears to offer a survival advantage; however, this may reflect tumour location and volume. Prospective studies are necessary to compare activity of combination doxorubicin-piroxicam to currently applied therapies.

Adjuvant therapy with carboplatin and pamidronate for canine appendicular osteosarcoma

Amputation and chemotherapy are the mainstay of treatment for canine appendicular osteosarcoma (OSA). In vitro studies have demonstrated anti-tumour activity of pamidronate against canine OSA. The purpose of this study was to assess the safety of adding pamidronate to standard post-operative carboplatin chemotherapy in 17 dogs with appendicular OSA treated with limb amputation. Median disease-free interval (DFI) and median survival time (MST) were evaluated as secondary endpoints. Incidence of side effects and treatment outcomes were compared to 14 contemporary control patients treated with carboplatin alone. There were no identified side effects to the pamidronate treatment. The median DFI for the study group was 185 days compared to 172 days for the control group (P = 0.90). The MST of the study group was 311 days compared to 294 days for the control group (P = 0.89). Addition of pamidronate to carboplatin chemotherapy for the treatment of canine appendicular OSA is safe and does not impair efficacy of standard carboplatin treatment.

The use, publication and future directions of immunocytochemistry in veterinary medicine: a consensus of the Oncology‐Pathology Working Group

One of the primary objectives of the Oncology Pathology Working Group (OPWG), a joint initiative of the Veterinary Cancer Society and the American College of Veterinary Pathologists, is for oncologists and pathologists to collaboratively generate consensus documents to standardize aspects of and provide guidelines for oncologic pathology. Consensus is established through review of relevant peer-reviewed literature relative to a subgroups particular focus. In this document, the authors provide descriptions of the literature reviewed, the review process, and a summary of the information gathered on immunocytochemistry. The intent of this publication is to help educate practitioners and pathologists on the process of immunocytochemistry and to provide a guide for the use of this technique in veterinary medicine. This document represents the opinions of the working group and the authors and does not constitute a formal endorsement by the American College of Veterinary Pathologists or the Veterinary Cancer Society.

Potency and stability of compounded cyclophosphamide: a pilot study.

Compounding of drugs for use in veterinary oncology is becoming increasingly common. We obtained 15 mg cyclophosphamide capsules from five different compounding pharmacies and performed potency analyses at two time points, as well as stability at 60 days. Potency results for four out of five and zero out of five (4/10) samples analysed were inadequate. Stability at 60 days was acceptable for all but one sample. This pilot study raises several important points of concern when compounding chemotherapy in dogs and cats. Further studies are necessary to solidify this data. Collaboration between pharmacists, veterinarians and regulatory bodies is needed to ensure safe and accurate delivery of compounded drugs to client-owned animals.

Vinblastine as a second rescue for the treatment of canine multicentric lymphoma in 39 cases (2005 to 2014)

OBJECTIVES The objective of this study was to retrospectively evaluate response and outcome of dogs with multicentric lymphoma treated with single-agent vinblastine as a second rescue. METHODS Medical records from 39 client-owned dogs receiving vinblastine rescue treatment (having relapsed on or following completion of UW-Madison and CCNU/L-asparaginase protocols), between 2005 and 2014, were reviewed for information regarding clinical presentation, diagnostic testing, drug dosage, number of treatments, side effects, response and outcome. RESULTS The median starting dose of vinblastine was 2·6 mg/m(2) (1·7 to 2·8 mg/m(2) ), administered weekly until disease progression. Of the 39 dogs treated, 3 dogs (7·7%) achieved a complete remission, 7 dogs (17·9%) achieved a partial response, 18 dogs (46·2%) maintained stable disease and 11 (28·2%) had progressive disease. Ten dogs (25·6%) developed a grade III or IV neutropenia, and 4 dogs (10·3%) developed grade III or IV thrombocytopenia (one dog in both categories). After starting vinblastine, the median progression-free survival was 29·5 days (0 to 77 days) and overall median survival time was 46 days (4 to 250 days). Duration of first remission was identified as a positive predictor of outcome. CLINICAL SIGNIFICANCE Single-agent vinblastine is well tolerated in dogs with relapsed or refractory lymphoma. Responses were incomplete and short-lasting.

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.

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.