Paul E. Miller

Central Nervous System Neosporosis in a Foal

Cutaneous or subcutaneous cysts of all types are considered rare in cats. A literature search yielded no reports of cutaneous or subcutaneous dermoid cysts in cats. The structures reported here were histologically compatible with the description of the dorsal midline structures in dogs but, because they did not communicate with the spinal canal, these cysts posed no danger or potential danger to the animal from central nervous system infection. These structures were present in the flank instead of along the dorsal midline, possibly as a result of faulty embryologic fusion of adjacent dermatomes. The dermoid cyst in cat no. 2, considering its young age, probably was a congenital disorder; however, cat no. 1 was 10 years old at the time of presentation. It was not known how long the cyst in cat 1 had been present or if it had grown in size immediately prior to presentation. Dermoid cysts have been classified according to depth of penetration of the sinus. Class I cysts extend from the skin to the supraspinous ligament, class II cysts do not extend as deeply but are connected to the supraspinous ligament by a fibrous band, and class III cysts are similar to class II cysts but have no connecting band to the ligament. A fourth class has been proposed, in which the cyst extends to the spinal canal and is attached to the dura mater. This class is analogous to the pilonidal sinus of human beings, which usually occurs in the coccygeal region. The term pilonidal cyst, which by definition means any cyst containing a tuft of hair, is usually used synonymously with the term dermoid cyst in veterinary medicine. Perhaps 1 reason for the confusion over the term dermoid cyst is that many deep anomalous structures can have structural components of epithelium and can be loosely termed dermoid cysts by pathologists. A recent textbook has subclassified these cysts in an effort to more clearly define each type from a histologic standpoint. In this classification system, dermoid cysts are considered a type of follicular tumor. More widespread application of the classification system may be helpful to pathologists and clinicians for separating benign lesions from those with potential for serious complications. The surgical treatment of dermoid cysts is straightforward and involves careful dissection of the cyst. Although dermoid cysts are reported to involve only the skin or subcutaneous tissues, the cyst in cat no. 1 was found isolated between muscle layers of the flank and the sinus in cat no. 2 extended to the peritoneum. When excision of the cyst involves creation of an abdominal wall defect, care should be taken to ensure that anatomic closure of the defect is accomplished to avoid subsequent herniation of abdominal contents.

Myofibroblastic sarcoma originating at the site of rabies vaccination in a cat

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Effects of the Application of Neck Pressure by a Collar or Harness on Intraocular Pressure in Dogs

The effect on intraocular pressure (IOP) from dogs pulling against a collar or a harness was evaluated in 51 eyes of 26 dogs. The force each dog generated while pulling against a collar or a harness was measured. Intraocular pressure measurements were obtained during application of corresponding pressures via collars or harnesses. Intraocular pressure increased significantly from baseline when pressure was applied via a collar but not via a harness. Based on the results of the study, dogs with weak or thin corneas, glaucoma, or conditions for which an increase in IOP could be harmful should wear a harness instead of a collar, especially during exercise or activity.

The pharmacologic assessment of a novel lymphocyte function-associated antigen-1 antagonist (SAR 1118) for the treatment of keratoconjunctivitis sicca in dogs.

PURPOSE Keratoconjunctivitis sicca (KCS) is characterized by inflammation and decreased production of tears containing increased levels of cytokines. The release occurs in the setting of conjunctival and lacrimal gland inflammation, potentially mediated by the interaction between lymphocyte function-associated antigen (LFA)-1, a cell surface protein found on lymphocytes, and its cognate ligand intercellular adhesion molecule (ICAM)-1. SAR 1118 is a novel LFA-1 antagonist and may be an effective therapeutic agent for the treatment of KCS. The following studies were performed to assess the in vitro activity of SAR 1118 and to evaluate the clinical efficacy of topical SAR 1118 for the treatment of idiopathic canine KCS. METHOD Pharmacodynamics were assessed by measuring the ability of SAR 1118 to inhibit Jurkat T-cell binding with recombinant human ICAM-1 and to inhibit cytokine release from human peripheral blood mononuclear cells (PBMCs) stimulated by staphylococcal enterotoxin B. For the assessment of clinical efficacy, 10 dogs diagnosed with idiopathic KCS were treated with SAR 1118 1% topical ophthalmic solution three times daily for 12 weeks. Schirmers tear test (STT) was used to measure tear production. RESULTS SAR 1118 demonstrated concentration-dependent inhibition of Jurkat T-cell attachment, inhibition of lymphocyte activation, and release of inflammatory cytokines, particularly the Th1, Th2, and Th17 T-cell cytokines IFN-γ, IL-2, and IL-17F, respectively. Mean STT values increased from 3.4 mm during week 1 to 5.8 mm at week 12 (P < 0.025). No SAR 1118-related adverse events were observed. CONCLUSIONS SAR 1118 appears to be an effective anti-inflammatory treatment for KCS. Additional studies are warranted to establish the efficacy of SAR 1118 for the treatment of KCS in humans.

Feline Glaucoma – A Comprehensive Review

Cats with glaucoma typically present late in the course of disease. It is likely that glaucoma in cats is under-diagnosed due to its insidious onset and gradual progression, as well as limitations of some commonly used tonometers in this species. Treatment of glaucoma in feline patients presents a clinical challenge, particularly as glaucoma is often secondary to other disease processes in cats. In this review, we consider the clinical features, pathophysiology, and classification of the feline glaucomas and provide current evidence to direct selection of appropriate treatment strategies for feline glaucoma patients.

Prevention of Experimental Choroidal Neovascularization and Resolution of Active Lesions by VEGF Trap in Nonhuman Primates

OBJECTIVE To evaluate the efficacy of systemic and intravitreous administration of VEGF Trap (aflibercept) in a nonhuman primate model of choroidal neovascularization (CNV). METHODS VEGF Trap treatment on laser-induced CNV was evaluated in 48 adult cynomolgus monkeys. In the prevention arms of the study, VEGF Trap was administered by intravenous injection (3 or 10 mg/kg weekly) or intravitreous injection (50, 250, or 500 μg/eye every 2 weeks) beginning before laser injury. In the treatment arm, a single intravitreous injection (500 μg) was given 2 weeks following laser injury. Laser-induced lesions were scored from grade 1 (no hyperfluorescence) to grade 4 (clinically relevant leakage). Representative lesions were evaluated histologically. RESULTS Grade 4 leakage developed at 32.4% and 45.4% of the laser sites in animals receiving intravitreous or intravenous administration of placebo at 2 weeks following laser injury, respectively. In contrast, the development of grade 4 lesions was completely or nearly completely prevented in all groups receiving intravenous or intravitreous injections of VEGF Trap. A single intravitreous injection of VEGF Trap (500 μg) administered following the development of CNV reduced the frequency of grade 4 lesions from 44.4% to 0% within 14 days of treatment. Intravitreous VEGF Trap was well tolerated with either no or only mild ocular inflammation. Histological evaluation showed decreased scores for morphologic features of tissue proliferation in the VEGF Trap prevention groups. CONCLUSIONS VEGF Trap prevented the development of clinically relevant CNV leakage when administered at the lowest doses tested. Moreover, a single intravitreous injection induced inhibition of active CNV leakage. CLINICAL RELEVANCE The animal model used in this study has an established track record as a predictor of pharmacologic efficacy of antineovascular drugs in humans having the neovascular, or wet, form of age-related macular degeneration.

Safety and Biodistribution of an Equine Infectious Anemia Virus-Based Gene Therapy, RetinoStat®, for Age-Related Macular Degeneration

RetinoStat(®) is an equine infectious anemia virus-based lentiviral gene therapy vector that expresses the angiostatic proteins endostatin and angiostatin that is delivered via a subretinal injection for the treatment of the wet form of age-related macular degeneration. We initiated 6-month safety and biodistribution studies in two species; rhesus macaques and Dutch belted rabbits. After subretinal administration of RetinoStat the level of human endostatin and angiostatin proteins in the vitreous of treated rabbit eyes peaked at ∼1 month after dosing and remained elevated for the duration of the study. Regular ocular examinations revealed a mild to moderate transient ocular inflammation that resolved within 1 month of dosing in both species. There were no significant long-term changes in the electroretinograms or intraocular pressure measurements in either rabbits or macaques postdosing compared with the baseline reading in RetinoStat-treated eyes. Histological evaluation did not reveal any structural changes in the eye although there was an infiltration of mononuclear cells in the vitreous, retina, and choroid. No antibodies to any of the RetinoStat vector components or the transgenes could be detected in the serum from either species, and biodistribution analysis demonstrated that the RetinoStat vector was maintained within the ocular compartment. In summary, these studies found RetinoStat to be well tolerated, localized, and capable of persistent expression after subretinal delivery.

Refractive states of eyes and association between ametropia and breed in dogs

OBJECTIVE To assess the refractive state of eyes in various breeds of dogs to identify breeds susceptible to ametropias. ANIMALS 1,440 dogs representing 90 breeds. PROCEDURES In each dog, 1 drop of 1% cyclopentolate or 1% tropicamide was applied to each eye, and a Canine Eye Registration Foundation examination was performed. Approximately 30 minutes after drops were administered, the refractive state of each eye was assessed via streak retinoscopy. Dogs were considered ametropic (myopic or hyperopic) when the mean refractive state (the resting focus of the eye at rest relative to visual infinity) exceeded +/- 0.5 diopter (D). Anisometropia was diagnosed when the refractive error of each eye in a pair differed by > 1 D. RESULTS Mean +/- SD refractive state of all eyes examined was -0.05 +/- 1.36 D (emmetropia). Breeds in which the mean refractive state was myopic (< or = -0.5 D) included Rottweiler, Collie, Miniature Schnauzer, and Toy Poodle. Degree of myopia increased with increasing age across all breeds. Breeds in which the mean refractive state was hyperopic (> or = +0.5 D) included Australian Shepherd, Alaskan Malamute, and Bouvier des Flandres. Astigmatism was detected in 1% (14/1,440) of adult (> or = 1 year of age) dogs; prevalence of astigmatism among German Shepherd Dogs was 3.3% (3/90). Anisometropia was detected in 6% (87/1,440) of all dogs and in 8.9% (8/90) of German Shepherd Dogs. CONCLUSIONS AND CLINICAL RELEVANCE Refractive states of canine eyes varied widely and were influenced by breed and age. In dogs expected to have high visual function (eg, performance dogs), determination of refractive state is recommended prior to intensive training.

Ocular Adverse Events Associated with Antibody–Drug Conjugates in Human Clinical Trials

This article reviews ocular adverse events (AEs) reported in association with administration of antibody-drug conjugates (ADCs) in human clinical trials. References reporting ocular toxicity or AEs associated with ADCs were collected using online publication searches. Articles, abstracts, or citations were included if they cited ocular toxicities or vision-impairing AEs with a confirmed or suspected association with ADC administration. Twenty-two references were found citing ocular or vision-impairing AEs in association with ADC administration. All references reported use of ADCs in human clinical trials for treatment of various malignancies. The molecular target and cytotoxic agent varied depending on the ADC used. Ocular AEs affected a diversity of ocular tissues. The most commonly reported AEs involved the ocular surface and included blurred vision, dry eye, and corneal abnormalities (including microcystic corneal disease). Most ocular AEs were not severe (≤ grade 2) or dose limiting. Clinical outcomes were not consistently reported, but when specified, most AEs improved or resolved with cessation of treatment or with ameliorative therapy. A diverse range of ocular AEs are reported in association with administration of ADCs for the treatment of cancer. The toxicologic mechanism(s) and pathogenesis of such events are not well understood, but most are mild in severity and reversible. Drug development and medical professionals should be aware of the clinical features of these events to facilitate early recognition and intervention in the assessment of preclinical development programs and in human clinical trials.

Effects of topical administration of latanoprost, timolol, or a combination of latanoprost and timolol on intraocular pressure, pupil size, and heart rate in clinically normal dogs

OBJECTIVE To determine effects after topical administration of latanoprost, timolol, or a commercially available latanoprosttimolol combination twice daily on intraocular pressure (IOP), pupil size (PS), and heart rate (HR) in clinically normal dogs. ANIMALS 17 clinically normal dogs. PROCEDURES A randomized controlled clinical trial was performed with a treatment (n=9) and saline (0.9% NaCl) solution group (8). Each dog in the treatment group received 3 treatments (latanoprost, timolol, and the latanoprost-timolol combination), with a 14-day washout period between treatments. Baseline values were established on day 1 of each treatment period. On days 2 through 5, drugs were administered topically every 12 hours to 1 eye of each dog in the treatment group. In both groups, IOP PS, and HR were measured at 0, 2, 4, 6, 8, and 9 hours on days 2 and 5. RESULTS Eyes treated with latanoprost or the latanoprost-timolol combination had a significant decrease in IOP and a significantly smaller PS, compared with results for dogs receiving only timolol or dogs in the saline solution group. Timolol and the latanoprost-timolol combination both significantly lowered HR, compared with HR following administration of latanoprost and the saline solution. CONCLUSIONS AND CLINICAL RELEVANCE Topical administration of latanoprost alone was as effective at lowering IOP as was administration of the latanoprost-timolol combination when both were given every 12 hours to clinically normal dogs. Timolol, either alone or in combination with latanoprost, appeared to have little or no effect on IOP in clinically normal dogs but was associated with a reduction in HR.