Treatment of corneal squamous cell carcinoma using topical 1% 5‐fluorouracil as monotherapy

The purpose of this report is to discuss the use of topical 1% 5‐fluorouracil as a sole therapy for canine corneal squamous cell carcinoma (SCC). A 12‐year‐old castrated male pug was evaluated for a well‐demarcated, central, 3 mm in diameter, pale pink, raised, right corneal mass. An incisional biopsy was obtained using a #64 beaver blade after topical anesthesia and without sedation. A definitive diagnosis of corneal SCC was obtained after histopathologic evaluation of the biopsy. Topical 1% 5‐fluorouracil ointment was applied to the right eye four times daily for 2 weeks followed by no treatment for 2 weeks, then treatment again twice daily for 2 weeks. The cornea remained free of recurrence 10 months after cessation of treatment. In dogs affected with corneal SCC, topical 1% 5‐fluorouracil monotherapy may be a viable and cost‐effective treatment option with minimal side effects. This chemotherapy agent may also have an effect on corneal pigmentation. Chronic cyclosporine therapy did not contribute to the pathogenesis of corneal SCC in the case described.     

Multiple papillomavirus-associated epidermal hamartomas and squamous cell carcinomas in situ in a dog following chronic treatment with prednisone and cyclosporine

A 4-year-old, spayed female toy fox terrier developed multiple epidermal hamartomas and squamous cell carcinomas in situ following chronic immunosuppressive therapy with prednisone and cyclosporine for management of an immune-mediated nonregenerative anaemia. Immunohistochemical staining was positive for papillomavirus antigen within both benign (n = 19) and malignant (n = 8) cutaneous lesions that developed during a 3-year period of observation, with positive staining most often seen in keratinocytes in the granular cell layer. Treatment of the papillomavirus infection with interferon-alpha was discontinued after 2 weeks because of diarrhoea and a further increase in liver enzymes. The cutaneous lesions of this dog persisted and new lesions developed during the year following discontinuation of both cyclosporine and prednisone. This is the first reported case of papillomavirus-associated squamous cell carcinoma in situ developing in a dog following chronic administration of cyclosporine and prednisone.     

Multicentric lymphoma in a dog after cyclosporine therapy

An 11-year-old, neutered male German shepherd dog was presented with perianal ulceration and fistulas. A clinical diagnosis of anal furunculosis was made, and the dog was treated with cyclosporine and ketoconazole. The perianal lesions resolved. However, after four weeks of therapy the dog developed multicentric lymphoma. Complete remission was achieved with combination chemotherapy (Wisconsin-Madison protocol). Cyclosporine administration is associated with an increased risk of development of lymphoma in humans and a similar increased risk might be expected in dogs. Although a causative relationship between cyclosporine administration and the development of lymphoma cannot be proven in this case, it is possible that cyclosporine therapy may have contributed to lymphomagenesis. As the use of cyclosporine in small animals is increasing, further work is required to substantiate and quantify the proposed increased risk.     

Generalized lymphadenopathy resembling lymphoma in cats: six cases (1972-1976)

Six cases of prominent generalized peripheral lymphadenopathy in the cat were reviewed. The lymph node biopsy specimens of these cats had many histologic features of lymphoma. One cat was euthanatized after the initial diagnosis of lymphoma. In the other 5 cats, the lymphadenopathy regressed without therapy within 1 to 17 weeks.     

Retrobulbar pigmented peripheral nerve sheath tumor in a dog

A 1‐year‐old male castrated Pug was referred for unilateral exophthalmos unresponsive to oral antibiotic and anti‐inflammatory therapy. Clinical findings included exophthalmos of the left eye with lateral strabismus, resistance to retropulsion, and an elevated nictitans. Hematologic and biochemical analyses were within normal limits. Findings following computed tomography (CT) of the head included an expansile retrobulbar soft tissue mass with bony lysis extending into the left nasal cavity and nasopharynx. Ultrasound‐guided fine‐needle aspirates and biopsy samples obtained via rhinoscopy were nondiagnostic. Palliative exenteration was elected; the patient was euthanized 13 weeks following exenteration due to development of neurologic signs and perceived poor quality of life. The histopathologic diagnosis was a malignant pigmented peripheral nerve sheath tumor.     

Keratoconjunctivitis sicca exacerbation in a dog treated with systemic atenolol

A 6‐year‐old, intact, male English cocker spaniel was referred for treatment of chronic conjunctivitis and unilateral keratitis. The dog was diagnosed with bilateral immune‐mediated keratoconjunctivitis sicca, treated with topical cyclosporine 0·2% ointment and sodium hyaluronate eye drops and improved considerably. After 2 months, pulmonic stenosis was diagnosed, and the dog commenced treatment with oral atenolol; the ophthalmological disease worsened dramatically within a few days. The ophthalmic signs rapidly improved after discontinuation of atenolol, and there was bilateral complete remission after 3 weeks. No oral β‐blocker therapy was reintroduced, and thereafter, keratoconjunctivitis sicca was well‐controlled with topical therapy.     

Clinical trial evaluating the efficacy and safety of cyclosporine in dogs with atopic dermatitis

OBJECTIVE: To determine efficacy and safety of cyclosporine in the treatment of atopic dermatitis among dogs in North America. DESIGN: Randomized controlled (phase 1) and open-label (phase 2) trials. ANIMALS: 268 dogs with atopic dermatitis. PROCEDURE: In phase 1, dogs were randomly assigned to be treated with cyclosporine (5 mg/kg [2.3 mg/Ib], PO, q 24 h) or a placebo. In phase 2, all dogs were treated with cyclosporine for 16 weeks. Frequency of cyclosporine administration was decreased if dogs improved clinically. RESULTS: At the end of phase 1, canine atopic dermatitis extent and severity index (CADESI) scores for dogs treated with cyclosporine were significantly lower than scores for control dogs. Percentage of dogs with severe pruritus decreased from 67% to 16% for the cyclosporine group but from 66% to only 61% for the control group. During phase 2, cyclosporine dosage was decreased to every-other-day administration in 39% of the dogs after 4 weeks. After 12 weeks, 22% of the dogs were treated twice weekly and 36% were treated every other day. After 16 weeks, CADESI score had decreased > 50% in 68% of the dogs and 47% of dogs had no or mild pruritus. The most frequent adverse reactions were gastrointestinal tract signs. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that cyclosporine is efficacious for the treatment of atopic dermatitis in dogs and that frequency of cyclosporine administration can be reduced following an initial induction period. The drug was well tolerated.     

Results of clinical renal transplantation in 15 dogs using triple drug immunosuppressive therapy

OBJECTIVE: To evaluate outcome of renal transplantation in dogs administered cyclosporine, azathioprine, and prednisolone immunosuppression. STUDY DESIGN: Prospective clinical study. ANIMALS: Fifteen dogs with chronic renal failure. RESULTS: Nine dogs died within 1 month of surgery; 5 died from complications associated with generalized thromboembolism. Three dogs survived for 6-25 months. Three dogs alive at the time of this report have survived 22-48 months; however, all 3 dogs have had bacterial infections that responded to antibiotic therapy. There was no biochemical evidence of acute allograft rejection in any dog. Perioperative use of enoxaparin may have prevented thromboembolism in 5 dogs. CONCLUSIONS: Triple drug immunosuppressive therapy used in this study prevented acute renal allograft rejection in 6 dogs that survived >4 weeks; however, immunosuppression was excessive, resulting in an unacceptable frequency of infection and other drug-related complications. Perioperative anticoagulation therapy seem to be warranted. CLINICAL RELEVANCE: Survival time and quality of life for this group of dogs was poor; however, there was no evidence of acute rejection in the dogs surviving >4 weeks. This protocol should only be used if the degree of immunosuppression is reduced, and early evidence of allograft rejection is monitored by renal biopsy or markers of lymphocyte activation.     

Idiopathic thrombocytopenic purpura in a cat

An 11-year-old, castrated, male domestic shorthair cat was presented for hematuria and pollakiuria. The cat had a marked thrombocytopenia, and a bone-marrow core biopsy demonstrated megakaryocytic hyperplasia with many megakaryocyte-associated neutrophils (i.e., emperipolesis). On peripheral blood, collected at initial presentation, what appeared to be platelets were noted to be within or adherent to occasional neutrophils. The thrombocytopenia was idiopathic in that no definitive cause could be found. However, platelet concentrations appeared to increase and decrease in response to changes in prednisone and cyclosporine therapy, suggesting a possible immune-mediated pathogenesis. As tests to detect increased feline platelet-associated antibodies are unavailable, immune-mediated thrombocytopenia can only be tentatively diagnosed in cats by exclusion and response to therapy.     

Phase II study of oral docetaxel and cyclosporine in canine epithelial cancer

The goal of the current study was to determine the efficacy of oral docetaxel in combination with cyclosporine in the treatment of canine epithelial cancer. Requirements for eligibility were histological confirmation of epithelial neoplasia, measurable disease, no chemotherapy treatment within 2 weeks, and a life expectancy of ≥3 months. Fifty‐one dogs were enrolled. All dogs received 1.625 mg kg^?1 of docetaxel with 5 mg kg^?1 of cyclosporine (DT/CSA) by gavage. Ten dogs had progressive disease at 2 weeks, one dog died, and one dog was withdrawn from the study. Thirty‐nine dogs were given a second dose of DT/CSA, three each receiving a third or fourth dose. Eight dogs had a dose reduction (1.5 mg kg^?1) and six dogs had treatment delays primarily for gastrointestinal toxicity. The overall response rate was 16.7% (8/48 had a partial response there were no complete responses). The highest response rate was seen in dogs with oral squamous cell carcinoma (50%; 6/12).     

Clinical use of cyclosporine as an adjunctive therapy in the management of feline idiopathic pure red cell aplasia

The clinical use of cyclosporine is described in a group of client-owned cats diagnosed with idiopathic pure red cell aplasia (PRCA). All 10 cats were treated with combinations of glucocorticoids and cyclosporine. Of the 10 cats, the eight for which follow-up data was available achieved and maintained remission for a median of 31 and 406 days, respectively. Therapy was reduced or discontinued in 7/8 cats; 2/7 maintained remission off therapy and 5/7 cats relapsed. Remission was reinduced in four cats, with 3/4 cats maintained long-term on low dose therapy. Adverse effects associated with cyclosporine therapy were responsive to dose reduction or drug withdrawal. Feline idiopathic PRCA was responsive to combination immunosuppressive therapy with glucocorticoids and cyclosporine. Relapse was common, particularly after drug discontinuation; therefore, most cats required maintenance long-term low dose therapy.     

Episcleral cyclosporine A implants for the management of unilateral keratoconjunctivitis sicca in an 8‐year‐old mare

An 8‐year‐old mare was presented for investigation of a 1‐month history of blepharospasm, eyelid swelling, corneal edema, and ocular discharge of the right eye (OD). Ophthalmic examination confirmed mucopurulent ocular discharge, conjunctival hyperemia, and a dry, dull appearance to the cornea OD. Schirmer tear test results confirmed an absence of tear production OD (0 mm/min) consistent with keratoconjunctivitis sicca. Treatment with topical 0.2% cyclosporine A resulted in an improvement in clinical signs. An episcleral cyclosporine A implant was placed under standing sedation 5 days after initial presentation. Re‐examination 9 days post‐operatively confirmed that the mare's tear production in the right eye had improved and no further clinical signs had been observed. Topical medications were gradually discontinued. Re‐examinations performed up to 12 months postsurgery showed no recurrence of clinical signs and no adverse effects of the implant. To our knowledge, this is the first report of the use of a cyclosporine A implant in the management of KCS in a horse and highlights its potential as an effective, alternative therapy in the management of KCS in horses.     

Dogs with acute myeloid leukemia or lymphoid neoplasms (large cell lymphoma or acute lymphoblastic leukemia) may have indistinguishable mediastinal masses on radiographs

Acute myeloid leukemia is an uncommon hematopoietic neoplasm of dogs that should be differentiated from lymphoid neoplasms, such as lymphoma, because of different treatment protocols and a worse prognosis. Thoracic radiography is performed frequently in dogs with suspected hematopoietic neoplasia, and detecting a mediastinal mass often prioritizes lymphoma as the most likely diagnosis. However, we have observed a mediastinal mass in several dogs with acute myeloid leukemia and hypothesized that (1) the frequency of a mediastinal mass was higher and (2) the size of the mass was larger in dogs with acute myeloid leukemia compared to dogs with lymphoid neoplasms. In this analytical study (observational, retrospective, and cross‐sectional), the sample population included 238 dogs with hematopoietic neoplasia. These dogs were divided into lymphoid (large cell lymphoma, acute lymphoblastic leukemia) and myeloid groups based on standard phenotyping tests. A mediastinal mass was detected during thoracic radiography in 73/218 (33%) and nine of 20 (45%) dogs in the lymphoid and myeloid groups (P = 0.21), respectively. The median size ratio of mediastinal mass to cardiac silhouette was 0.20 and 0.23 in the lymphoid and myeloid groups (P = 0.96), respectively. Additionally, we observed normal thoracic radiographs in 111/218 (51%) dogs in the lymphoid group and nine of 20 (45%) dogs in the myeloid group. In conclusion, acute myeloid leukemia should be considered when a mediastinal mass is detected during radiography in dogs with suspected hematopoietic neoplasia—but the presence or size of a mediastinal mass does not differentiate between myeloid and lymphoid neoplasms.     

Cyclosporine A affects the in vitro expression of T cell activation-related molecules and cytokines in dogs

Cyclosporine is a powerful immunosuppressive drug that is being used with increasing frequency to treat a wide range of immune-mediated diseases in the dog. To date, ideal dosing protocols that will achieve immunosuppression with cyclosporine in dogs remain unclear, and standard methods that can measure effectiveness of immunosuppression have not been established. The aim of our study was to evaluate the effects of in vitro cyclosporine exposure on a panel of molecules expressed by activated T cells to ascertain their potential as biomarkers of immunosuppression in dogs. Blood was drawn from six healthy dogs, and peripheral blood mononuclear cells (PBMC) were isolated and activated. Half of the cells were incubated with 200 ng/mL cyclosporine prior to activation, and the other half were not exposed to cyclosporine. Samples were analyzed using flow cytometry, and the expression of intracellular cytokines IL-2, IL-4, and IFN-γ was evaluated after 6, 12, and 24h of drug exposure. Each cytokine exhibited a time-dependent suppression profile, and all but two samples activated in the presence of cyclosporine showed lower cytokine expression than untreated controls. We also evaluated the expression of the surface T cell activation molecules CD25 and CD95 by flow cytometry after 36 h of drug exposure. Expression of these surface molecules decreased significantly when activated in the presence of cyclosporine. Our results suggest that suppressed expression of the markers related to T cell activation could potentially be utilized as an indicator of the efficacy of cyclosporine therapy in dogs.     

A novel population of cells in the peripheral blood of a cow with a neurofibrosarcoma

An unusual population of leukocytes was observed in the peripheral blood of a cow with a large tumor burden, using flow microfluorimetry. This new population accounted for 50% of the total cells in the peripheral blood of this animal. These cells expressed the p150,95 molecule (bovine CD11c equivalent), identified by the monoclonal antibody C5B6, a molecule found on myeloid cells and activated lymphocytes. The new population did not express the pan T molecules BoCD2 (the bovine T11 equivalent), BoCD5 (the bovine CD5 equivalent) or surface IgM. Isolated peripheral blood mononuclear cells maintained in bulk culture were able to kill autologous tumor cells and BHV-1 infected A549 in an NK-like assay. In vitro cytotoxicity by cells cultured from the peripheral blood of this animal was augmented 2- to 4-fold by the addition of IL-2.     

TOTAL BODY IRRADIATION FOR THE TREATMENT OF LYMPHOMA IN A GUINEA PIG (CAVIA PORCELLUS)

A 5-year-old intact male guinea pig was evaluated for a 2-week history of “red eyes.” Sniffling and lethargy had been noticed for several days as well. Physical examination findings included increased expiratory effort and bilateral chemosis. Several peripheral lymph nodes were markedly enlarged. Fine needle aspiration of the enlarged lymph nodes was consistent with lymphoma. The first total body irradiation with 1 Gray (Gy) resulted in a good response as evidenced by a decrease in lymphocytes and reduced sizes of the enlarged peripheral lymph nodes. The second total body irradiation with 1.2 Gy was performed 49 days after the first total body irradiation because of tumor progression. This resulted in a less noticeable response compared to the first response, including slight shrinkage of the affected lymph node. Thus, the patient was euthanized 4 weeks after the second total body irradiation. This is the first report that describes radiation therapy for spontaneously occurring lymphoma in a guinea pig.     

Intracranial metastases from an ovarian dysgerminoma in a 2-year-old dog.

A 2-year-old, intact female rottweiler was presented for signs of lethargy. A mass was ultrasonographically observed, cranial and lateral to the left kidney. Exploratory laparotomy revealed a mass in the left ovary that was diagnosed histopathologically as an ovarian dysgerminoma. Two weeks after surgery, the dog was readmitted with signs of peripheral vestibular disease that progressed to central vestibular disease. Magnetic resonance imaging of the brain revealed the presence of a mass in the caudal fossa. The histopathological diagnosis of the mass was metastases from the ovarian dysgerminoma.     

Identification of a c-kit exon 8 internal tandem duplication in a feline mast cell tumor case and its favorable response to the tyrosine kinase inhibitor imatinib mesylate

The gain-of-function mutations within c-kit, a protooncogene encoding KIT, induce constitutive ligand-independent kinase activation and are important for the pathogenesis of mast cell proliferative disease in humans as well as in dogs. Despite the clinical importance of feline mast cell tumors, no mutation has been shown within the c-kit gene in cats. In the present report, we analyzed the c-kit nucleotide sequence in the case of a cat that showed systemic mastocytosis and mastocytemia. Within the c-kit cDNA prepared from the malignant mast cells, we identified an 12-bp internal tandem duplication at the region corresponding to exon 8, resulting in a four amino acid insertion between residues Thr418 and His419 within the fifth immunoglobulin-like domain of KIT. The cat underwent therapy with the kinase inhibitor imatinib mesylate (Gleevec) at a dose of 10mg/kg. The tumor masses greatly responded and were undetectable after 5 weeks of treatment. Correspondingly, the number of mast cells in the peripheral blood was markedly reduced. It is, therefore, considered that the internal tandem duplication within the domain contributes to the neoplastic transformation of mast cells in the cat by increasing KIT phosphorylation.     

Periocular neurofibrosarcoma in a horse

A periocular neurofibrosarcoma was debulked and treated with intralesional cisplatin in a 5-year-old Thoroughbred mare. The horse presented with a 1-year history of a large slowly progressing subcutaneous mass over the right supraorbital process. The mass was surgically debulked, and intralesional cisplatin (1.0 mg/cm3) was injected in 3 doses at 2 weeks, 5 weeks, and 8 weeks postoperatively. No recurrence was noted over a 15-month follow-up period. Histopathology of the mass indicated neurofibrosarcoma.     

Successful Treatment of Disseminated Nocardiosis Caused by Nocardia veterana in a Dog

A 5‐year‐old male castrated Lhasa Apso cross was evaluated for a 1‐month history of inappetence, lethargy, gagging, and progressive right thoracic limb lameness. Synovial fluid analysis revealed nonseptic suppurative inflammation, and a diagnosis of immune‐mediated polyarthritis (IMPA) was made. After 3 months of treatment with prednisone and later cyclosporine, the dog developed multiple firm cutaneous and subcutaneous masses and a focal mass within the jejunum. Cultures of blood, urine, skin lesions, and the jejunal mass identified Nocardia veterana by matrix‐absorption laser desorption ionization‐time‐of‐flight mass spectrometry (MALDI‐TOF MS) and allowed for earlier identification of the organism compared to more traditional secA1 gene sequencing. Immunosuppressive drug treatment was discontinued, and the dog was treated for 3 months by administration of trimethoprim‐sulfamethoxazole (TMS). No recurrence of clinical signs was reported 1 year later. This case report highlights the clinical utility of MALDI‐TOF MS, particularly for the rapid identification of slow‐growing, fastidious organisms.