KEY WORDSReovirus, SCID mice, cancer biotherapy, distal necrosis, vasculitis, myocarditis ACKNOWLEDGEMENTSThe authors would like to thank Calgary Laboratory Services for salary support (D.J.D.) and assistance with the histology studies. Oncolytics and Dr. Matt Coffey are gratefully acknowledged for their funding of the immunostaining costs of the project. The Patrick Lee laboratory is acknowledged for the gift of SCID mice treated with reovirus, and the anti-reovirus sera. The Don Morris laboratory is also acknowledged for the gift of mouse specimens. Research Paper Morbidity in Immunosuppressed (SCID/NOD) Mice Treated with Reovirus (Dearing 3) as an Anti-Cancer Biotherapeutic ABSTRACTSpecific viral oncolysis of cancer cells has aroused great interest as a potential anti-cancer therapy. Reovirus was proposed as an anti-cancer biotherapeutic several years ago, as it elicits virus-mediated death of human cancer cells both in vitro and in mouse model systems. A common model system for reovirus oncolysis is the NOD/ LtSz-scid/scid (SCID/NOD) immunocomprimised mouse. While human tumour xenografts are effectively killed by intra-tumour injections of reovirus, the mice often exhibit discoloration and necrosis of extremities including feet, distal leg, tail and ears several weeks after injection. This phenomenon never occurs in sham-injected mice, nor is it observed in wild type or nude mice. The pathogenesis of this "Black Foot" lesion has not yet been described, but may be of relevance for future human studies of biotherapeutics.Examination of SCID/NOD mice was performed at various time points following intratumoral injection of reovirus. Immunohistological evaluation of tissues reveals infection of cardiac myocytes and venous endothelial cells at approximately 2 days post infection. Over time, venules and veins showed a mixed inflammatory vasculitis and thrombus formation. Synchronously, the heart showed diffuse myocyte death, with dystrophic calcification. The results indicate that the "Black Foot" syndrome is likely due to venous vasculitis secondary to reovirus infection, on a background of reovirus myocarditis and heart failure. The rationale for the selective susceptibility of venous over arterial endothelium to reovirus infection is currently unknown. The results of this study may be relevant to the use of oncolytic viruses, particularly reovirus, in the anti-cancer therapy of immunosuppressed patients.

In this model, magnesium deficiency results in sudden cardiac death. The presence of startle induction of sudden death preceded by seizures suggests that sudden cardiac death results from a neurologic trigger.

Epicardial APD dispersion decreases in hypertrophied hearts following an increase in afterload, and this response is mediated in part by the absence of afterload-induced shortening of the APD. This effect may be due in part to altered responses of the delayed rectifying current to cardiac loading conditions in the setting of cardiac hypertrophy.

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The peritoneal epithelial lesions in 40 cases of proliferating ovarian serous tumour are described. The lesions were varied and of both neoplastic and non-neoplastic form. The most common was serous tumour similar to that in the associated ovarian neoplasm. Tumour of this type was present in some or all of the peritoneal lesions in 77.5% of cases. In nearly two-thirds, the tumour was superficial; in the rest it invaded omentum. Occasionally, the infiltrating tumour was poorly differentiated. Benign tubular lesions resembling endosalpingiosis occurred in 16 (40%) of the 40 cases, but in seven it was associated with serous tumour. Psammoma bodies frequently accompanied serous tumour and endosalpingiosis and in occasional cases the majority of lesions consisted of psammomatous foci. The duration of follow up is too short to adequately assess the biological significance of these findings but it is clear that the peritoneal tumour occasionally may kill the patient within a few years. 'Serous tumour of low malignant potential' is the most appropriate term to describe the general group of ovarian serous tumours of so-called 'borderline malignant' type.