Randomized trial of cisplatin versus firocoxib versus cisplatin/firocoxib in dogs with transitional cell carcinoma of the urinary bladder.

BACKGROUND: Cisplatin combined with a nonselective cyclooxygenase (cox) inhibitor has potent antitumor activity against transitional cell carcinoma (TCC) in dogs, but this treatment is limited by renal toxicosis. Cox-2 is expressed in TCC, but only in limited sites within the kidney. A cox-2 inhibitor could enhance the antitumor activity of cisplatin with potentially fewer adverse effects on the kidney. HYPOTHESIS: Cisplatin/cox-2 inhibitor treatment will have greater antitumor activity but no more renal toxicosis than cisplatin alone in dogs with TCC. ANIMALS: Forty-four dogs with naturally occurring urinary bladder TCC. METHODS: Dogs were randomized to receive cisplatin (60 mg/m(2) IV q21d), firocoxib (5 mg/kg PO q24h), or the combination. Tumor measurements were determined before and at 6-week intervals during treatment. Renal function was monitored by serum creatinine concentration, iohexol clearance, and urine specific gravity. Toxicoses were graded according to Veterinary Co-Operative Oncology Group (VCOG) criteria. RESULTS: The remission rate with cisplatin/firocoxib (57%) was significantly (P = .021) higher than that with cisplatin alone (13%). Renal and gastrointestinal toxicoses were common in dogs receiving cisplatin, but there were no significant differences between dogs receiving cisplatin or cisplatin/firocoxib. Firocoxib alone induced partial remission or stable disease in 20 and 33% of dogs, respectively. CONCLUSIONS: Firocoxib significantly enhanced the antitumor activity of cisplatin resulting in partial remission in more than half of the cases. The toxicoses inherent to cisplatin, however, were noted in dogs receiving this combination. Firocoxib had antitumor effects as a single agent and can be considered a palliative treatment for dogs with TCC.

Cyclin D3 expression in normal fetal, normal adult and neoplastic feline tissue.

Cyclin D3 is a tightly regulated cell cycle protein and member of the cyclin D family-a group of proteins that facilitates the progression of a cell through G(1) and into the S phase of the cell cycle. All cells use at least one of the cyclin D proteins for cell cycle regulation. In this study, feline tissues (normal fetal and adult, and neoplastic) were examined immunohistochemically for expression and topographical distribution of cyclin D3. Its distribution was similar to that in human tissues in health and neoplasia, and suggested a dual role of cyclin D3 in cell proliferation and differentiation. Immature lymphoid tissue and proliferating epithelial cells in health and neoplasia were immunoreactive for cyclin D3, whereas expression of the protein in other immunoreactive tissues reflected differentiated cell types. Immunoreactivity for cyclin D3 was particularly striking in germinal centre cells of normal lymph nodes and B-cell lymphomas, and in normal suprabasal epithelial cells of the skin and mucous membranes of the oropharynx and in squamous cell carcinomas at these sites.

Middle ear tumours with brainstem extension treated by ventral bulla osteotomy and craniectomy in two cats.

Two geriatric domestic shorthaired cats (DSH) were treated surgically with a ventral bulla osteotomy and craniectomy for middle ear tumours that invaded the calvarium. Both cats had a history of vestibular disease. One cat had a normal neurological examination. Both cats underwent computed tomographic imaging of the head. After intravenous injection of an iodinated contrast material, one cat had a ring-enhancing intracranial lesion and the other had a uniform contrast-enhancing intracranial lesion, which either communicated with the bulla or was associated with bulla osseous lysis/production. One cat had a papillary adenoma and the other had an adenocarcinoma. Both cats had prolonged survivals (630 days; alive and lost to follow-up at 840 days), which is longer than reported in cats with middle ear neoplasia. Craniectomy, in addition to ventral bulla osteotomy, may be part of the treatment plan for middle ear tumours that invade the calvarium.

Non-coherent light for photodynamic therapy of superficial tumours in animals.

Cultured 9L cells were incubated with varying concentrations of pheophorbide-a-hexyl ether (HPPH) and then exposed to 665-nm red light from a non-coherent light source or a dye laser. Cell death was produced by both light sources, with the non-coherent light being most effective at the highest HPPH concentrations. To assess the feasibility of using the non-coherent light source for clinical photodynamic therapy (PDT), four dogs and three cats presenting with spontaneous superficial tumours were injected intravenously with 0.15 mg kg(-1) of HPPH, 1 h before their tumours were irradiated with 665-nm non-coherent light (50 mW cm(-2), 100 J cm(-2)). Of the nine tumours treated, there were eight complete responses, all occurring in animals with squamous cell carcinoma. After 68 weeks of follow-up, the median initial disease-free interval had not been reached. These data suggest that non-coherent light sources may be efficacious for photodynamic therapy of spontaneous superficial tumours in animals, representing a cost-effective alternative to medical lasers in both veterinary and human oncology.

T-cell-derived malignant lymphoma in the boxer breed.

The boxer breed of dog is at high risk for a variety of neoplasms including lymphoma. In this observational study, tissue sections from boxer dogs with lymphoma were immunostained for T and B lymphocyte distinction, and the results compared with similar studies carried out on lymphoma tissues from temporally selected cohorts of golden retriever and rottweiler dogs. The frequency of T-cell lymphomas was significantly (P < 0.001 for all comparisons) higher in the boxers than in the rottweilers or golden retrievers. We are unaware of other reports linking immunotype of canine lymphoma with breed; whether other brachycephalic breeds of dogs have a similar preponderance of T-cell lymphoma awaits further study.

Preclinical evaluation of 5-aminolevulinic acid-based photodynamic therapy for canine transitional cell carcinoma.

As a prelude to photodynamic therapy, 5-aminolevulinic acid (ALA) was given orally to healthy dogs. ALA-induced protoporphyrin IX (PpIX) fluorescence significantly increased in the mucosa of the urinary bladder in an ALA dose-dependent fashion. Vomiting occurred after ALA administration in 70% of the dogs but did not affect PpIX fluorescence. ALA-based photodynamic therapy (PDT) of the urinary bladder in healthy dogs caused only submucosal oedema within the bladder wall. No haematologic or serum biochemistry abnormalities were observed after ALA administration. Microscopic haematuria was observed in all the dogs after PDT but was mild and self limiting. ALA-based PDT was administered to six dogs with transitional cell carcinoma (TCC) of the lower urinary tract. ALA-based PDT resulted in tumour progression-free intervals from 4 to 34 weeks in five dogs; one dog with pre-existing hydronephrosis died shortly after PDT. Dogs with TCC represent an outbred, spontaneous, tumour model for developing PDT protocols for humans with bladder cancer.

Tissue levels, histologic changes and plasma pharmacokinetics of meta-Tetra (hydroxyphenyl) chlorin (mTHPC) in the cat.

The biodistribution and pharmacokinetics of meta-tetra(hydroxyphenyl)chlorin (mTHPC)(1) have been documented in humans, rats, dogs and rabbits. It has been demonstrated to be an effective photodynamic therapy agent for treatment of squamous cell carcinoma. Squamous cell carcinoma is a common feline neoplasm, causing significant morbidity and mortality in the feline population. The association between ultraviolet radiation exposure and occurrence of this neoplasm in the cat provides a useful model for the study of human cutaneous squamous cell carcinoma. In this study, we document the biodistribution, pharmacokinetics and toxicity of mTHPC in a group of normal cats. Four groups of cats were given the drug intravenously at dosages of 0, 0.15, 0.30 and 0.60 mg/kg. mTHPC levels were measured in plasma and tissues at 0, 24, 48, 72, 96 and 336 h after drug administration. Additionally, plasma samples were collected at 1 and 6 h post-injection and analysed. Biodistribution and pharmacokinetics of mTHPC in cats mirrors that in other animal species. There were no clinical or pathological changes associated with administration of the drug. The biodistribution and pharmacokinetics of mTHPC in cats mirrors that in other species studied. There were no clinical or pathological changes attributable to administration of the drug at the doses administered. mTHPC may be a useful photodynamic therapy drug in cats.

Osteosarcoma of the patella with pulmonary metastases in a dog.

A 6-year-old neutered male Rottweiler was examined for a progressive right pelvic limb lameness. In radiographs of the right stifle, there was an osteolytic lesion with irregular new bone formation along the cranial aspect of the patella consistent with an aggressive bone lesion. In thoracic radiographs, there were multiple soft tissue nodular opacities throughout the lung fields, consistent with pulmonary metastases. Microscopically, fine needle aspirate samples from the right patella contained pleomorphic spindle cells with cytologic features of osteosarcoma. The presence of pulmonary metastases at the time of initial diagnosis in the dog described herein suggests that osteosarcoma of the patella has the potential for similar aggressive biologic behavior as that seen in dogs with appendicular osteosarcoma.

Clinical outcome and diseases associated with extreme neutrophilic leukocytosis in cats: 104 cases (1991-1999).

OBJECTIVE: To describe diseases, prognosis, and clinical outcomes associated with extreme neutrophilic leukocytosis in cats. DESIGN: Retrospective study. ANIMALS: 104 cats with extreme neutrophilic leukocytosis. PROCEDURE: Medical records from 1991 to 1999 were examined to identify cats that had > or =50,000 WBC/microl with > or =50% neutrophils. Signalment, absolute and differential WBC counts, rectal temperature, clinical or pathologic diagnosis, duration and cost of hospitalization, and survival time were reviewed. RESULTS: Mean age of cats was 8.3 years, mean WBC count was 73,055 cells/microl, and mean absolute neutrophil count was 59,046 cells/microl. Mean duration of hospitalization was 5.9 days, and mean cost of hospitalization was $2,010. Twenty-nine (28%) cats were febrile, and 63 (61%) cats died. Overall median survival time was 30 days. Cats with neoplasia were nearly 14 times as likely to die unexpectedly as cats with other diseases. CONCLUSIONS AND CLINICAL RELEVANCE: Extreme neutrophilic leukocytosis was associated with a high mortality rate. The prognostic importance of extreme neutrophilic leukocytosis should not be overlooked. Cats and dogs have similar diseases, mortality rates, and treatment costs associated with extreme neutrophilic leukocytosis.

Preclinical study in cats of the pro-photosensitizer 5-aminolevulinic acid.

OBJECTIVE: To determine whether feline cells were able to convert 5-aminolevulinic acid (ALA) to protoporphyrin IX (PpIX) in vivo and in vitro, whether i.v. administration of ALA to healthy cats resulted in adverse effects, and whether PpIX accumulated in a squamous cell carcinoma (SCC) of a cat. ANIMALS: 4 healthy adult cats and 1 adult cat with a cutaneous SCC. PROCEDURE: In vitro production of PpIX was determined by incubating Crandell feline kidney cells with ALA. Effects of ALA administration and in vivo production of PpIX were determined by administering ALA (100, 200, or 400 mg/kg of body weight) to healthy cats and collecting skin biopsy specimens for up to 24 hours after drug administration. Blood samples were collected for CBC and serum biochemical analyses, and necropsies were performed. Accumulation of PpIX in a SCC was determined by treating a cat with a facial SCC with ALA and collecting specimens of the tumor and adjacent grossly normal skin. RESULTS: Incubation of ALA with feline cells resulted in time- and dose-dependent cytoplasmic accumulation of PpIX in vitro. After i.v. ALA administration, PpIX was detected in all tissues examined, with the highest fluorescence intensity in epithelia and in squamous cell carcinoma. The tumor-to-skin fluorescence intensity ratio was 5. All cats developed hepatotoxicoses. CONCLUSIONS AND CLINICAL RELEVANCE: Results from this limited number of cats suggest that ALA may be a useful photosensitizer in cats, but that doses > 100 mg/kg, i.v., may not be safe.

Outcome of surgical versus medical treatment of dogs with beta cell neoplasia: 39 cases (1990-1997).

OBJECTIVE: To compare outcome of surgical versus medical treatment of dogs with beta cell neoplasia. DESIGN: Retrospective study. ANIMALS: 39 dogs with clinical signs of hypoglycemia and serum glucose and insulin concentrations consistent with a diagnosis of beta cell neoplasia. PROCEDURE: Information on signalment; clinical history; physical examination findings; results of CBC, serum biochemical analyses, and urinalysis; serum glucose and insulin concentrations; results of thoracic radiography and abdominal ultrasonography; treatment and treatment complications; survival time; and cause of death were obtained from medical records. RESULTS: 26 dogs underwent exploratory celiotomy and partial pancreatectomy; 13 dogs were treated medically (i.e., dietary change and prednisone). Median survival time was significantly longer for dogs treated surgically than for dogs treated medically. Significant differences were not found in mean age, body weight, duration of clinical signs prior to diagnosis, serum glucose and insulin concentration, or results of other serum biochemical tests between dogs treated surgically and dogs treated medically; also, there was no significant correlation between any of these parameters and survival time for either group of dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that exploratory celiotomy and partial pancreatectomy are indicated once a tentative diagnosis of beta cell neoplasia is established in dogs.

Low-intensity laser light-induced closure of a chronic wound in a dog.

OBJECTIVE: To describe the application of low-intensity laser light for treatment of a chronic, full-thickness skin wound in a dog. STUDY DESIGN: Case report. ANIMALS: An 8-year old, castrated Whippet. METHODS: The wound was irradiated on the awake patient with 630 nM wavelength, nonthermal red light once daily for 4 consecutive days. Changes in wound surface area were measured by computer analysis of digital images of the wound. RESULTS: The wound diminished in size during the course of laser treatments and was completely healed by day 21. No post-treatment complications occurred. CONCLUSIONS: Low-intensity laser light may be useful for treatment of chronic skin wounds in dogs.

Clinical outcome and associated diseases in dogs with leukocytosis and neutrophilia: 118 cases (1996-1998)

OBJECTIVE: To describe diseases, prognosis, and clinical outcomes associated with leukocytosis and neutrophilia in dogs. DESIGN: Retrospective study. ANIMALS: 118 dogs with leukocytosis and neutrophilia. PROCEDURE: Medical records from 1996 to 1998 were examined for dogs with WBC > or = 50,000 cells/microliter and neutrophilia > or = 50%. Signalment, absolute and differential WBC counts, body temperature, clinical or pathologic diagnosis, duration and cost of hospitalization, and survival time were reviewed. RESULTS: Mean age was 7.7 years, WBC count was 65,795 cells/microliter, and absolute neutrophil count was 53,798 cells/microliter. Mean duration of hospitalization was 7.4 days and cost of hospitalization was $2,028.00. Forty (34%) dogs were febrile, and 73 (62%) dogs died. Overall median survival time was 17 days. Dogs with neoplasia or fever were more likely to die than dogs that were hospitalized or had systemic or local infections. CLINICAL IMPLICATIONS: Leukocytosis and neutrophilia were associated with high mortality rate and have prognostic value. Given the mean duration and cost of hospitalization, frank discussion with an owner at first recognition of leukocytosis and neutrophilia may be warranted.

Computer-assisted image analysis of intratumoral vessel density in mammary tumors from dogs.

OBJECTIVE: To determine whether intratumoral microvessel density can be used to distinguish benign from malignant mammary tumors in dogs and to predict the outcome of surgical treatment for small volume (< 3-cm diameter) tumors. SAMPLE POPULATION: Tissue sections from 58 mammary tumors (42 malignant and 16 benign) from dogs. PROCEDURE: Mammary tumors were stained by immunohistochemistry for factor VIII-related antigen. Computer-assisted image analysis was used to determine intratumoral vessel density in immunostained areas. Total vascular density (TVD), calculated from 3 non-overlapping fields, was analyzed for correlation with patient or tumor histomorphologic characteristics, and results obtained by surgical treatment of small volume tumors. RESULTS: Mean TVD of malignant tumors was significantly greater than that of benign tumors. Total vascular density was not correlated with patient age, sex, reproductive status, clinical tumor stage, or histologic type. For small volume (< 3-cm diameter) malignant tumors, mean TVD was higher in tumors that recurred after surgery than in tumors that did not recur; however, TVD was not predictive of time to recurrence. CONCLUSION AND CLINICAL IMPLICATIONS: Immunohistochemistry and computer-assisted image analysis allowed objective quantitation of intratumoral microvessel density in formalin-fixed, paraffin-embedded tissue sections. Tumors with high TVD were more likely to recur after surgical treatment than tumors with low TVD suggesting that TVD measurements can be used by the clinician, in addition to histologic type and clinical stage, to predict prognosis after surgical treatment. These data also provide rationale for use of antiangiogenesis strategies for treatment of malignant mammary tumors in dogs.

Results of chemotherapy for cats with alimentary malignant lymphoma: 21 cases (1993-1997)

OBJECTIVE: To determine clinical and pathologic findings in cats with alimentary malignant lymphoma and results of treatment with a combination of prednisone, L-asparaginase, vincristine, cyclophosphamide, doxorubicin, and methotrexate. DESIGN: Retrospective study. ANIMALS: 21 cats with alimentary malignant lymphoma. PROCEDURE: Medical records were reviewed, and information on signalment, clinical history and signs, previous treatments, and results of laboratory tests, thoracic radiography, and abdominal ultrasonography were obtained. RESULTS: Test results in all cats were negative for FeLV; 3 of 19 were positive for feline immunodeficiency virus. Thirteen tumors were stage III, 7 were stage IV, and 1 was stage V. Diagnosis was confirmed on the basis of microscopic examination of histologic (n = 13) or cytologic (8) specimens. Immunophenotyping was performed on 13 tumors; 10 were T-cell and 3 were B-cell lymphomas. Overall median duration of first remission was 20 weeks. Overall median survival time was 40 weeks. The only factor significantly associated with duration of first remission was whether cats had a complete response following induction chemotherapy; duration of first remission was significantly associated with survival time. Cats tolerated treatment well; only 1 cat had a delay in the treatment schedule because of neutropenia. CLINICAL IMPLICATIONS: Use of a multidrug chemotherapeutic protocol that includes L-asparaginase and doxorubicin results in minimal adverse effects and prolonged survival times in cats with alimentary malignant lymphoma.

Evaluation of single-agent mitoxantrone as chemotherapy for relapsing canine lymphoma.

Many chemotherapeutic regimens will induce remission in dogs with lymphoma, but almost all dogs suffer relapse. Mitoxantrone was selected for evaluation as single-agent chemotherapy for relapsing canine lymphoma based on its use in humans undergoing salvage chemotherapy for non-Hodgkin's lymphoma and its tumoricidal effect against canine lymphoma. Dogs entered into study had multicentric lymphoma, and all had been treated solely with a standard combination chemotherapy protocol. At 1st relapse, all dogs were again staged and underwent lymph node biopsy. Mitoxantrone was administered IV at 6 mg/m2 every 21 days. Dogs were evaluated for lymphadenopathy before each dose of mitoxantrone. Fifteen dogs were entered into study. The average age (+/- SEM) of the dogs studied was 7.7 +/- 0.91 years, and most dogs were large (mean +/- SEM weight, 24.44 +/- 2.15 kg). Twelve dogs (80%) had B-cell lymphoma, and 3 had T-cell lymphoma. Dogs were staged IV (n = 12) or V (n = 3). The median duration of chemotherapy before entry into the study was 98 days. Overall median duration of response after mitoxantrone chemotherapy was 21 days. Complete responses were attained in 7 of 15 dogs (47%) with a median response duration of 84 days. Nine of 15 (60%) dogs attained a complete remission with additional chemotherapy after failing mitoxantrone chemotherapy. Mild toxicities were observed after mitoxantrone administration. No adverse reactions were observed during mitoxantrone infusions. The results of this study demonstrate that mitoxantrone, as a single agent, has limited value for dogs with lymphoma at 1st relapse after conventional multidrug chemotherapy.

Photodynamic therapy in veterinary medicine: current status and implications for applications in human disease.

The historical development and published veterinary applications of photodynamic therapy are reviewed. Potential animal models, using naturally-occurring diseases in veterinary patients, for the future development of photodynamic therapy are described.