Veterinary Clinical Sciences - Theses
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ItemIsocitrate dehydrogenase 1 R132H: epidermal growth factor receptor and Ki-67 expression in canine gliomas( 2019)The diagnosis, histological classification and grading of canine gliomas can be challenging, particularly in the antemortem. In humans, it is essential to accurately diagnose gliomas as the treatment and prognosis vary between tumour histologic type and grade. Numerous biomarkers have been investigated to aid in the diagnosis and classification of human gliomas, including epidermal growth factor receptor (EGFR), Ki-67 and a point mutation in the isocitrate dehydrogenase 1 gene at codon 132 (IDH1 R132H). Only limited studies looking at these biomarkers have been performed in dogs, from which clear conclusion cannot be drawn. The prognosis for canine glial tumours is considered guarded to poor, with the current treatment options having limited success. Consequently, there is a lack of gold standard treatment for canine glioma. In humans, gliomas are being investigated at a molecular level to identify therapeutic targets and to improve responsiveness to treatment. Numerous molecular targets have been identified including EGFR and IDH1 R132H. Canine gliomas share many morphologic, histologic and immunohistochemical characteristics with human gliomas, suggesting a translational approach to the classification, treatment and prognostication of canine gliomas may be possible. The objectives of this research were: (1) to describe the signalment, presenting clinical signs, diagnostic findings, treatment and survival time of a series of dogs with glial tumours, (2) to investigate the series of canine gliomas for the IDH1 R132H mutation, and for EGFR and Ki-67 expression, utilising immunohistochemistry and (3) to determine if immunoreactivity is associated with tumour histologic type and grade. The clinical data of thirty-one dogs with histologically confirmed glial tumours was reviewed retrospectively. The formalin-fixed paraffin-embedded tumour specimens were evaluated for IDH1 R132H, pan-IDH1 (IDH1 wild-type and mutated IDH1), EGFR and Ki-67 expression. IDH1 R132H and pan-IDH1 expression were recorded as positive or negative. EGFR immunoreactivity was evaluated using a semi-quantitative score, and Ki-67 expression was expressed as the Ki-67 labelling index (LI). Patient signalment, clinical presenting signs and diagnostic investigation findings were similar to previous reports. The IDH1 R132H point mutation was not identified in any (0%) of the canine glial tumours, while all 31 (100%) tumours were positive for pan-IDH1 expression. EGFR expression was identified in 16/31 (51.6%) tumours and expression was significantly greater in high grade gliomas when compared to low grade tumours (P = 0.04). Furthermore, EGFR expression was significantly greater in gliomatosis cerebri when compared to oligodendroglioma (P = 0.002), astrocytoma (P = 0.01), and oligoastrocytoma (P = 0.04). Ki-67 expression was identified in 28/31 (90.3%) gliomas, and the Ki-67 LI was significantly higher in high grade tumours (P = 0.02). A significant moderate correlation between the Ki-67 LI and EGFR immunoreactivity (r = 0.47, P = 0.007) was identified. The IDH1 R132H point mutation was not identified in this series of canine gliomas, and may not be an appropriate biomarker to aid in the classification and treatment of these tumours. EGFR, however, may be a suitable therapeutic target, particularly for gliomatosis cerebri. The Ki-67 LI may aid in the development of a grading scheme for canine gliomas.
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ItemInflammation and endothelial perturbation in canine abdominal surgery: the potential modulatory effect of lidocaine( 2019)Complication rates following emergency laparotomy surgery are high, with organ dysfunction being a commonly encountered post-operative complication. Given the endothelium acts as the interface between the systemic circulation and the organs, its function is vital to maintaining organ health. The endothelium is in a constant state of flux, impacted largely by the local environment of which it is a part. In the presence of wide-spread systemic inflammation, inflammatory mediators precipitate change to the structure of the endothelial glycocalyx. These changes result in shedding of the endothelial glycocalyx and alteration of the endothelial phenotype. The endothelium may, as a result, lose the capacity to regulate vasomotor tone, and shift toward a pro-inflammatory and pro-coagulant state. This predisposes to reduced tissue oxygen delivery, and organ dysfunction may ensue. This thesis aimed to answer two key questions: does surgical trauma induced in canine patients undergoing emergent abdominal surgery invoke a systemic inflammatory response and subsequent endothelial activation? And if so, does lidocaine, a proposed immunomodulatory drug, mitigate this effect when given in the post-operative period? Chapter two provides a detailed review of endothelial structure and function, and current literature pertaining to systemic inflammation and endothelial activation in the context of abdominal surgery. Chapter two also examines the literature regarding the proposed mechanisms through which lidocaine acts as an immunomodulatory drug, and reviews publications that investigate the use of lidocaine as an anti-inflammatory drug in human patients after abdominal surgery. Chapter three is a randomized, blinded clinical trial quantifying the effect of emergency abdominal surgery on the concentration of markers of systemic inflammation and endothelial perturbation in canine patients in the post-operative period. The trial also assessed the potential use of lidocaine as a post-operative immunomodulatory therapy in dogs having undergone laparotomy. Fifty canine patients undergoing abdominal surgery were enrolled in the study. Patients were randomized into two separate groups: a study group receiving lidocaine intravenously, and a control group receiving 0.9% NaCl intravenously for a twelve-hour period following abdominal surgery. Blood samples were gathered prior to surgery, followed by six and twelve hours post-operatively. Concentrations of markers of systemic inflammation (IL-6) and markers of endothelial perturbation (VEGF and HA) were quantified via means of ELISA at each time point. Results revealed a significant increase in the concentration of markers of systemic inflammation and endothelial perturbation in post-operative blood samples. No immunomodulatory or endothelial preserving effect of lidocaine was appreciated.