Recording of suspected adverse drug reaction reporting in veterinary free-text clinical narratives.

OBJECTIVES: To use text mining approaches to identify instances of suspected adverse drug reactions recorded in first opinion veterinary free-text clinical narratives, and to evaluate whether these were also reported to either the Veterinary Medicines Directorate or the relevant Marketing Authorisation holder in order to derive an estimate of the suspected adverse drug reaction (sADR) minimum under-reporting rate. To characterise sADR reports and explore whether particular features are associated with report submission. MATERIALS AND METHODS: Two regular expressions were developed to identify mentions of "adverse drug reactions" and "side effects" in the free-text clinical narratives of electronic health records contained within the Small Animal Veterinary Surveillance Network database. Consultations containing a match for the developed regular expressions were manually reviewed for inclusion and further classified to determine the suspected product, seriousness and expectedness of the event, and an indication of whether the event had been reported. The associations between event characteristics and reporting were explored using Fisher's exact tests. RESULTS: A total of 10,565 records were manually reviewed from which 827 sADRs were identified. Approximately 90% of these sADRs were not recorded as reported. Suspected adverse drug reactions that were not considered "expected" were recorded as reported more frequently than "expected" sADRs. However, clinical severity did not appear to impact on whether there was a record of reporting. CLINICAL SIGNIFICANCE: This is the first estimate of under reporting sADRs based on real world evidence from veterinary clinical records. The under-reporting rate implied by this study highlights that further interventions are required to improve reporting rate within the veterinary profession in order to support pharmacovigilance activities and improve drug safety.

Molecular pathology in the cancer clinic - where are we now and where are we headed?

Molecular pathology is a developing sub-microscopic discipline of pathology that studies the effects of molecular variations and mutations on disease processes. The ultimate goal of molecular pathology in cancer is to predict risk, facilitate diagnosis and improve prognostication based on a complete understanding of the biological impact of specific molecular variations, mutations and dysregulations. This knowledge will provide the basis for customised cancer treatment, so-called precision medicine. Rapid developments in genomics have placed this field at the forefront of clinical molecular pathology and there are already a number of well-established genetic tests available for clinical use including PCR of antigen receptor rearrangement and KIT mutational analysis. Moving beyond tests assessing a single gene, there are significant research efforts utilising genomics to predict cancer risk, forecast aggressive behaviour and identify druggable mutations and therapeutic biomarkers. Researchers are also investigating the use of circulating cells and nucleic acid for clinically useful low morbidity genomic assessments. If we are to realise the full potential of molecular pathology and precision medicine there are a number of challenges to overcome. These include developing our understanding of the underlying biology (in particular intra-tumoural heterogeneity), methodological standardisation of assays, provision of adequate infrastructure and production of novel therapeutics backed by high-quality clinical data supporting the precision medicine approach. The era of molecular pathology holds the potential to revolutionise veterinary cancer care, but its impact on clinical practice will depend upon the extent to which the inherent challenges can be overcome.

Altered Nuclear Expression of the Deubiquitylase BAP1 Cannot be Used as a Prognostic Marker for Canine Melanoma.

BRCA1-associated protein-1 (BAP1) is a nuclear localized deubiquitylating enzyme that belongs to the ubiquitin c-terminal hydrolase subfamily. The encoded protein is highly homologous between man and dogs, suggesting a functional significance preserved by evolution. BAP1 has multiple properties, including tumour suppressor activity. Loss of BAP1 function is implicated in the oncogenesis of several types of cancers including uveal, mucosal and some cutaneous melanomas in humans, as well as in mesothelioma. In this study we investigate the significance of BAP1 in canine melanoma. Nuclear BAP1 protein was detected in five canine oral melanoma cell lines using an antibody commonly used for analysis of human tissues. BAP1 loss of function mutations often lead to loss of nuclear BAP1 (nBAP1) expression in humans; this is associated with a poorer prognosis in uveal and mucosal melanoma. Therefore, as a prelude to a study evaluating the prognostic significance of nBAP1 expression in dogs, immunohistochemistry (IHC) was used to assess cases of canine melanoma for nBAP1 expression. In 89 cases where tumour cells were identified by melan-A labelling, 100% of tumour cells were positive for nBAP1 expression, including eight uveal tract and 29 oral mucosal melanomas. This finding indicates that BAP1 IHC cannot be used as a prognostic marker in canine uveal and mucosal melanoma. Moreover, this observation suggests that either BAP1 has a different functional significance in canine melanoma or that loss of BAP1 function is achieved by a different route. This is a novel finding that warrants further investigation to determine the comparative biological relevance.

Acute radiotherapy toxicity in 57 dogs with gross and microscopic mast cell tumours.

Mast cell tumours (MCTs) are commonly treated with radiation therapy, most often in a microscopic disease setting. Poorer outcomes are expected in patients with gross disease, and irradiation of gross disease may be associated with greater toxicity. The aim of this study was to compare acute radiation adverse events (AE) in dogs with gross and microscopic MCTs receiving radiotherapy. Fifty-seven dogs were included, 28 with gross disease and 29 with microscopic. In order to assess mucosal and skin toxicity, patients were assigned to 2 groups: head (29 patients, 14 patients with gross and 15 microscopic) and other sites (28 patients, 14 each). All were treated with external beam radiotherapy, and toxicity assessed at the end of treatment and 10 to 14 days later (first recheck). All patients developed some acute radiation toxicity by the end of the course. However, there was no difference in the severity of toxicity between gross and microscopic disease in either site group at either time point. The only variable associated with an increased frequency of grade 2 or 3 toxicity at the first recheck was the use of prednisolone prior to radiotherapy (P = .05). No other factors were identified which were associated with increased toxicity. For the head group, the site of highest grade toxicity was mucosa or, if included in the field, nasal planum, which was often more severely affected than the mucosa. No significant late toxicity was identified. Two dogs developed acute haematemesis during the radiotherapy course, but both completed the course without further events.

Evaluation of a multi-agent chemotherapy protocol combining lomustine, procarbazine and prednisolone (LPP) for the treatment of relapsed canine non-Hodgkin high-grade lymphomas.

The standard of care treatment for canine lymphoma is multi-agent chemotherapy containing prednisolone, cyclophosphamide, vincristine and an anthracycline such as doxorubicin (CHOP) or epirubicin (CEOP). Lomustine, vincristine, procarbazine, and prednisone (LOPP) has been evaluated as a rescue, with encouraging results; however, resistance to vincristine is likely in patients relapsing on CHOP/CEOP, and this agent may enhance LOPP toxicity without improving efficacy. The aim of this study was to evaluate responses to a modified-LOPP protocol that does not include vincristine (LPP) and is administered on a 21-day cycle. Medical records of dogs with high-grade multicentric lymphoma from 2012 to 2017 were reviewed. Dogs with relapsed lymphoma that received LPP as a rescue protocol were enrolled. Response, time from initiation to discontinuation (TTD) and toxicity of LPP were assessed. Forty-one dogs were included. Twenty-five dogs (61%) responded to LPP including 12 complete responses (CR) and 13 partial responses (PR). Responders had a significantly longer TTD (P < .001) compared to non-responders with 84 days for CR and 58 days for PR. Neutropenia was documented in 20 dogs (57%): 12 grade I to II, 8 grade III to IV. Thrombocytopenia was infrequent (20%): 5 grade I to II, 2 grade III to IV. Twelve dogs developed gastrointestinal toxicity (30%): 10 grade I to II and 2 grade III. Nineteen dogs had elevated ALT (59%): 9 grade I to II, 10 grade III to IV. Treatment was discontinued due to toxicity in 8 dogs (19%). The LPP protocol shows acceptable efficacy and toxicity-profile and minimizes in-hospital procedures.

Immunotherapy for canine cancer--is it time to go back to the future?

Over the last 50 years, the significance of the immune system in the development and control of cancer has been much debated. However, recent discoveries provide evidence for a role of immunological mechanisms in the detection and destruction of cancer cells. Forty years ago veterinary oncologists were already investigating the feasibility of treating neoplasia by enhancing anticancer immunity. Unfortunately, this research was hindered by lack of a detailed understanding of cancer immunology, this limited the specificity and success of these early approaches. The great forward strides made in our understanding of onco-immunology in recent years have provided the impetus for a resurgence of interest in anticancer immunotherapy for canine patients. In this article both these initial trials and the exciting novel immunotherapeutics currently in development are reviewed.

Toxicity associated with epirubicin treatments in a large case series of dogs.

Epirubicin is a stereoisomer of doxorubicin that is widely used in human oncology. The purpose of this study was to evaluate the toxicity associated with epirubicin administration in dogs. Three hundred and fifteen treatments were administered to 139 dogs. Patients received between one and seven doses. One hundred and sixteen treatments were associated with toxicity in 81 patients (50 episodes of lethargy, 49 of diarrhoea, 42 of vomiting, 40 of anorexia, 2 hypersensitivity reactions and 2 suspected extravasations). Thirty-six (11%) adverse events resulted in hospitalization in 33 (24%) patients, of which 15 were neutropenic and 9 pyrexic. Mean duration of hospitalization was 3.4 days and 33 patients recovered uneventfully. Owners of 11 patients declined further treatment after toxicity occurred. After 25 treatments associated with toxicity, dose reductions reduced toxicity. The use of prophylactic anti-emetics, gastroprotectants and antibiotics did not reduce the frequency of gastrointestinal toxicity.

Mast cell tumour and cutaneous histiocytoma excision wound healing in general practice.

OBJECTIVE: To assess whether wounds from incomplete mast cell tumour excisions are at greater risk of healing complications than wounds from complete excisions, or cutaneous histiocytomas. METHODS: Mast cell tumours and cutaneous histiocytomas submitted to Nationwide Laboratories between November 1, 2007 and April 30, 2008 were selected. Questionnaires were sent to submitting veterinarians requesting details of tumour characteristics, clinical approach to the tumour and wound healing. RESULTS: Three hundred and eighty-six mast cell tumours and 524 cutaneous histiocytomas were identified. One hundred and eighty-five mast cell tumours and 244 cutaneous histiocytomas questionnaires were returned (47% response). Wound complications arose in 20% of mast cell tumours and 21% of cutaneous histiocytomas. Multivariable analysis confirmed that larger tumours, tumours on the feet and a soft/"baggy" appearance, were significantly associated with a greater frequency of problems, leading to delayed wound healing and dehiscence. CLINICAL SIGNIFICANCE: Incomplete mast cell tumour excision does not lead to greater risk of wound complications. Mast cell tumour surgical wounds have a similar rate of wound complications as cutaneous histiocytoma wounds.