We compared clinical characteristics and outcomes for dogs with various digital tumors. Medical records and histology specimens of affected dogs from 9 veterinary institutions were reviewed. Risk factors examined included age, weight, sex, tumor site (hindlimb or forelimb), local tumor (T) stage, metastases, tumor type, and treatment modality. The Kaplan-Meier product limit method was used to determine the effect of postulated risk factors on local disease-free interval (LDFI), metastasis-free interval (MFI), and survival time (ST). Outcomes were thought to differ significantly between groups when P < or = .003. Sixty-four dogs were included. Squamous cell carcinoma (SCC) accounted for 33 (51.6%) of the tumors. Three dogs presented with or developed multiple digital SCC. Other diagnoses included malignant melanoma (MM) (n = 10; 15.6%), osteosarcoma (OSA) (n = 4; 6.3%), hemangiopericytoma (n = 3; 4.7%), benign soft tissue tumors (n = 5; 7.8%), and malignant soft tissue tumors (n = 9; 14%). Fourteen dogs with malignancies had black hair coats, including 5 of the 10 dogs with MM. Surgery was the most common treatment and, regardless of the procedure, had a positive impact on survival. None of the patient variables assessed, including age, sex, tumor type, site, and stage, had a significant impact on ST. Both LDFI and MFI were negatively affected by higher T stage, but not by type of malignancy. Although metastasis at diagnosis correlated with a shorter LDFI, it did not have a significant impact on ST. On the basis of these findings, early surgical intervention is advised for the treatment of dogs with digital tumors, regardless of tumor type or the presence of metastatic disease.

A 6-month-old, female border collie was referred for evaluation of hypocalcemia, hyperphosphatemia, fever, and painful ventral abdominal skin. She had recently been treated intravenously and subcutaneously (SC) with a diluted 10% calcium gluconate solution. The medical evaluation supported the diagnosis of primary hypoparathyroidism, but the subsequent hospital course was complicated by severe calcinosis cutis, which caused extensive skin necrosis and marked debilitation. This patient illustrates that administration of a calcium gluconate solution SC can be associated with extensive morbidity when administered to hyperphosphatemic patients.

OBJECTIVE To determine clinical response and toxic effects of cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (L-NDDP) administered i.v. at escalating doses to cats with oral squamous cell carcinoma (SCC). ANIMALS 18 cats with oral SCC. PROCEDURE Cats that failed to respond to conventional treatment or had nonresectable tumors were included. Data included a CBC, serum biochemical analyses, urinalysis, cytologic examination of a fine-needle aspirate of enlarged lymph nodes, and thoracic and oral radiographs for clinical staging. A starting dose (75 to 100 mg/m2 of L-NDDP) was administered i.v.. At 21-day intervals, subsequent doses increased by the rate of 5 or 10 mg/m2. Response was evaluated every 21 days by tumor measurement and thoracic radiography. Quality of life was assessed by owners, using a performance status questionnaire. RESULTS On average, cats received 2 treatments. Toxicoses included an intermittent, acute anaphylactoid-parasympathomimetic reaction, lethargy or sedation (< or = 24 hours), inappetence or signs of depression (< or = 72 hours), mild to moderate increase in hepatic enzyme activity, and melena. Pulmonary, renal, or hematopoietic abnormalities were not evident. Performance status surveys indicated normal behavior and grooming or decreased activity and self-care (19/20 assessments), ate well with or without assistance (15/20), and did not lose weight (15/20). Median survival time was 59.8 days (mean, 54.1 days). CONCLUSIONS AND CLINICAL RELEVANCE L-NDDP was ineffective for treatment of cats with oral SCC. None of the cats had a complete or partial remission. Acute toxicoses and poor therapeutic response limit therapeutic usefulness of L-NDDP in cats, unless dosage, frequency, and administration procedures can be improved.

Eighty-three canine cutaneous mast cell tumors were graded histologically and evaluated immunohistochemically for p53 tumor-suppressor protein expression. An avidin-biotin immunohistochemical protocol incorporated a rabbit polyclonal antibody (CM-1) directed against normal and mutant p53 protein. Positive staining was observed in 44.6% (37/83) of tumors and included 50% (12/24) of grade I (well differentiated) tumors, 46.9% (23/49) of grade II (intermediate differentiation) tumors, and 20% (2/10) of grade III (poorly differentiated) tumors. A statistically significantly higher proportion (P < 0.019) of tumors from the head and neck (83.3%, 10/12), stained positive for p53 than tumors from the thorax, back, abdomen, and axilla (39.4%, 13/33), legs (35.7%, 10/28), or prepuce, scrotal, or inguinal areas (44.4%, 4/9). No statistically significant difference between p53 labeling and histologic grade, breed, or tumor size was present. Survival data were available for 53/83 (63.9%) of dogs. Positive reactivity for p53 was observed in 47% (25/53) of tumors within this group, with 57.9% (11/19) of grade I, 43.3% (13/30) of grade II, and 25% (1/4) of grade III tumors labeled. Mean survival time for the 53 dogs was 12.1 months. The median survival time for dogs with grade III tumors or tumors >5 cm was statistically significantly shorter (P < 0.0001) than for dogs with grades I and II or smaller tumors. Although p53 protein abnormalities may play a role in tumor development or behavior in some canine cutaneous mast cell tumors, immunoreactivity was not associated with lack of tumor differentiation, tumor locations previously shown to demonstrate aggressive biological behavior, breed predisposition, or survival times.

Spontaneous canine oral melanoma (COM) is a highly metastatic cancer, resistant to chemotherapy, and can serve as a model for cancer immunotherapy. Liposome-encapsulated muramyl tripeptide-phosphatidylethanolamine (L-MTP-PE) can activate the tumoricidal activity of the monocyte-macrophage system following i.v. injection. The objective of these studies was to evaluate the therapeutic effectiveness of L-MTP-PE administered alone and combined with recombinant canine granulocyte macrophage colony-stimulating factor (rcGM-CSF) in dogs undergoing surgery for oral melanoma. Ninety-eight dogs with histologically confirmed, clinically staged, oral melanoma were entered into two randomized, double-blind, surgical adjuvant trials. In trial 1, 50 dogs were stratified based on clinical stage and randomized to once a week L-MTP-PE or lipid equivalent (control). When all of the clinical stages were combined, no difference in disease-free survival or in survival time (ST) were detected. However, within stage I, dogs receiving L-MTP-PE had a significant increase in ST compared with control, with 80% of the dogs treated with L-MTP-PE still alive at >2 years. Within each stage II and stage III, there was no difference detected between the treatment groups. In trial 2, 48 dogs were stratified on the basis of clinical stage and extent of surgery (simple resection or radical excision), treated with L-MTP-PE two times a week, and randomized to rcGM-CSF or saline (placebo) given s.c. daily for 9 weeks. Within each stage and when all of the stages were combined, there was no difference between the treatment groups. In both studies, stage I COM is associated with a better prognosis. No effect on survival was observed with regard to tumor location in the oral cavity, sex, type/extent of surgery, or age. In a subset of dogs tested, pulmonary alveolar macrophage cytotoxicity was enhanced with combined rcGM-CSF and L-MTP-PE but not in dogs treated with L-MTP-PE alone. The present study indicates that after surgery, L-MTP-PE administered alone or combined with rcGM-CSF showed no significant antitumor activity in treating advanced stage COM. In early stage COM, L-MTP-PE was shown to result in a prolongation of ST. Furthermore, this study provides additional rationale for the use of the dog model for human malignant melanoma.

OBJECTIVE:To determine adverse effects of single and multiple doses of liposome-encapsulated cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (L-NDDP) administered IV to healthy adult cats.ANIMALS:10 healthy adult cats.PROCEDURE:8 cats were given a single dose of L-NDDP (at rates of 75, 100, 150, or 200 mg/m2), and 2 cats were given liposomal lipid (1,500 mg/m2). Six of the 10 cats were given doses of L-NDDP at the maximum tolerated dosage (100 mg/m2) or a lower dosage (75 mg of L-NDDP/m2) at 21-day intervals, for a total of 4 treatments. Hematologic and serum biochemical analyses, urinalyses, and physical examinations were used to monitor effects of L-NDDP.RESULTS:All cats had transient pyrexia, lethargy, vomiting (1 to 3 times/24 h), inappetence, and an acute species-specific infusion reaction that was prevented by administration of atropine-diphenhydramine. Dose-limiting toxicosis was evident as a 10-day course of lethargy, intermittent vomiting, and diarrhea. In cats given multiple doses, dose-related thrombocytopenia, cumulative myelosuppression, transient increased hepatic transaminase activity, and mild to moderate hepatic hydropic degeneration and proximal renal tubular lipidosis in excess of lipidosis expected for this species were detected. Bone marrow hypoplasia was detected in some cats that received higher doses (cumulative dosages of 300 or 400 mg of L-NDDP/m2).CONCLUSION:Cats can safely be given L-NDDP at potentially therapeutic dosages without inducing renal or pulmonary toxicoses.CLINICAL RELEVANCE:Because L-NDDP has better tumoricidal activity than cisplatin (in vivo and in vitro) and is not cross resistant, it may be similarly or more efficacious than cisplatin in humans and dogs.

The use of autologous and allogenic bone marrow transplantations (BMT) in FIV-infected and uninfected cats is a novel therapy for feline hematopoietic diseases and retroviral infections. A total of 13 specific pathogen-free (SPF) cats received either autologous or allogenic BMT and seven of these cats were also infected with FIV before autologous or allogenic BMT. All BMT recipients received total body irradiation of 900 cGy just before BMT. Two FIV-infected and four uninfected cats received autologous uninfected BM cells cryopreserved before BMT. Five infected and two uninfected cats received BM cells from allogenic uninfected donors (RBC-, MHC-, and cross-matched). MHC-matching was based on mixed leucocyte reaction (MLR) and the donor-recipient combination which was compatible by MLR analysis, was used in this study. Recipients were monitored for hematology, immunology, virology, and clinical signs. All FIV-infected and uninfected recipients of autologous BMT had complete engraftment with minimal complications. Uninfected recipients of allogenic BMT had a more severe clinical episode with slower rate of engraftment. None of these BMT groups had mortality. In contrast, only two of the five infected recipients of allogenic BMT survived for a significant period of time (23 and 50 weeks) and rest of the cats succumbed to transfusion reactions. Both infected BMT groups had persistent CD4/CD8 inversion, low CD4+ cell counts, and FIV infection of engrafted peripheral blood mononuclear cells (PBMC). Overall, successful autologous and allogenic BMTs were performed in FIV-free cats. All infected recipients of autologous BMT had compete engraftment and are currently alive, with thelongest survival time being over 1 year. Thus, BMT in combination with antiviral drug therapies may be an alternative therapy against retroviral infection.

Eighty canine epithelial colorectal tumors obtained by excisional biopsy were evaluated immunohistochemically for p53 tumor suppressor gene protein. Dogs in the study average 6.9 years of age (range, 1-12.5 years). A standard avidin-biotin immunohistochemical protocol incorporated a polyclonal antibody of rabbit origin (CM-1) as the primary antibody. Positive staining was observed within all subcategories of lesions, including hyperplastic polyps 1/2 (50%), adenomas 14/29 (48%), carcinomas in situ 9/22 (41%), adenocarcinomas 3/4 (75%), and invasive carcinomas 8/23 (35%). A total of 35/80 (44%) positive tumors wee identified. Fifteen of 31 (48%) benign tumors labeled for p53 protein compared to 20/49 (41%) malignant tumors. Survival data was available for 57/80 (71%) dogs. The average age of dogs within the group with survival data was 4.4 years. Males predominated 34/57 (60%). Mean survival time was 20.6 months. There was no significant difference in survival time between dogs grouped according to p53 immunoreactivity, cellular stain location, or tumor site. A statistically significant increase in survival time was observed between dogs with clean surgical margins and those without (P < 0.018) and for dogs with adenomas or carcinomas in situ over dogs with invasive carcinomas (P < 0.02). In this study, the overall greater positive staining frequency of benign lesions compared to malignant lesions is contrary to data derived from similar immunohistochemical analyses of human tumors and is incongruous with the theorized late-stage participation of the p53 protein in the development of human colorectal cancers. The results of this study suggest that if the p53 tumor suppressor gene protein is involved in the progression of canine colorectal tumors, it may play a relatively early role, possibly analogous to the early appearance of p53 overexpression in precancerous lesions of human ulcerative colitis. Immunohistochemical detection of p53 was not useful prognostically.

OBJECTIVE:To characterize the frequency, clinical signs, biologic behavior, and response to treatment of tumors of the ear canal in dogs and cats.DESIGN:Retrospective analysis of medical records.ANIMALS:Medical records of 81 dogs (48 malignant tumors, 33 benign tumors) and 64 cats (56 malignant tumors, 8 benign tumors).PROCEDURE:Data were analyzed for cats and dogs with malignant tumors, and risk factors were analyzed for their potential impact on survival time.RESULTS:Malignant tumor types most commonly reported included ceruminous gland adenocarcinoma, squamous cell carcinoma, and carcinoma of undetermined origin. Median survival time of dogs with malignant aural tumors was > 58 months, whereas that of cats was 11.7 months. A poor prognosis was indicated by extensive tumor involvement (dogs) and by neurologic signs at time of diagnosis, diagnosis of squamous cell carcinoma or carcinoma of undetermined origin, and invasion into lymphatics or blood vessels (cats).CLINICAL IMPLICATIONS:Malignant tumors of the ear canal in dogs and cats have a propensity for local invasion, but tend not to metastasize. Squamous cell carcinoma and carcinoma of undetermined origin were the most locally aggressive tumors. Malignant tumors of the ear canal are best managed by aggressive surgical excision. Radiotherapy may be useful when tumors cannot be completely removed.

A 15-month-old 27.7-kg sexually intact male Doberman Pinscher was examined because of multiple subcutaneous abscesses on the neck, trunk, and limbs that developed 2 months after a dog bite and were refractory to antibiotic treatment. Incubation of a biopsy specimen at 37 C on a Lowenstein-Jensen agar slant for 8 days yielded growth of a Runyon's Group IV mycobacterium, and disseminated subcutaneous Mycobacterium sp infection was diagnosed. The organism was identified as M fortuitum, and was susceptible to amikacin, doxycycline, cefoxitin, minocycline, trimethoprim/sulfadiazine, and sulfisoxazole. Lesions resolved after 8 months of treatment with doxycycline (5 mg/kg of body weight, PO, q 12 h). The cause of dissemination was unknown; however, delay in debridement of the bite wound and corticosteroid use in initial wound management may have potentiated dissemination.

Forty cats with previously untreated, histologically confirmed mammary gland adenocarcinoma received a radical mastectomy of the affected mammary chain(s). All cats were stratified according to clinical stage and randomized to receive either weekly intravenous liposome-encapsulated muramyl tripeptide phosphatidylethanolamine or placebo (lipid-equivalent) for eight consecutive weeks in this double-blind study. Thirty-six of the 40 cats were available for follow-up. No significant differences in either disease-free interval or survival were found as a result of treatment. Cats with clinical stage II disease had a statistically significantly longer disease-free interval (p<0.02) and overall survival (p<0.005) when compared with clinical stage III cats.

Two randomized, double-blind clinical trials in dogs with spontaneous appendicular osteosarcoma treated with combination chemoimmunotherapy are reported. In both trials, dogs without overt metastasis underwent complete amputation of the affected limb. In trial 1, 40 dogs were treated with cisplatin chemotherapy [(CDDP), 70 mg/m2 i.v. every 28 days x 4]. Following CDDP, dogs without evidence of overt metastasis (n = 25) were randomized to receive liposome-encapsulated muramyl tripeptide phosphatidylethanolamine ](L-MTP-PE), 2 mg/m2 i.v.) or placebo liposomes (lipid equivalent) twice weekly for 8 weeks. Of 14 dogs in the placebo group, 13 (93%) died of metastasis; the median survival time was 9.8 months. Of 11 dogs in the L-MTP-PE group, 8 (73%) developed metastasis; the median survival time was 14.4 months, which was significantly longer than that of the placebo group (P < 0.01). In trial 2, 64 dogs received CDDP (70 mg/m2 i.v. every 21 days x 4) and were randomized to concurrently receive L-MTP-PE (2 mg/m2 i.v.) twice or once weekly, or placebo liposomes once weekly for 8 weeks. Median survival times were 10.3, 10.5, and 7.6 months, respectively. There were no significant differences among the three treatment groups in trial 2. Survival times for dogs receiving L-MTP-PE in trial 1 were significantly longer than those for dogs in trial 2 that received four doses of CDDP concurrently with twice weekly L-MTP-PE (P < 0. 04). The results of the first trial confirm our previous observation that L-MTP-PE has antimetastatic activity in dogs with osteosarcoma when given following amputation. The results of the second trial demonstrate that there is no survival advantage of administering L-MTP-PE concurrently with CDDP.

Targeted delivery of macrophage activating agents is an attractive approach to treat micrometastatic disease. Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) is a potent activator of monocytes/macrophages in humans, mice, and dogs. We have conducted clinical trials in dogs with malignant and highly metastatic spontaneous tumors. Presented are results of our trials evaluating L-MTP-PE in combination with surgery and chemotherapy in dogs with spontaneous osteosarcoma and hemangiosarcoma, particularly relevant malignancies having having many similarities to human cancer. Osteosarcoma dogs received chemotherapy following surgery (cisplatin q 28 days x 4). At completion of chemotherapy, dogs were randomized to receive L-MTP-PE or placebo. The L-MTP-PE group had a significantly longer median survival time compared to the placebo group (p < 0.021). Dogs with splenic hemangiosarcoma received combination chemotherapy following surgery (doxorubicin and cyclophosphamide q 21 days x 4). At the first chemotherapy, dogs were randomized to receive L-MTP-PE or placebo. The L-MTP-PE group had a significantly longer median survival time compared to the placebo group (p < 0.03). These studies show that L-MTP-PE is an effective agent for treatment of metastasis and can be safely administered in combination with chemotherapy.

Tumor necrosis factor-alpha (TNFalpha) and interleukin-6 (IL-6) are products of activated monocytes/macrophages with anti-tumor activity. Liposome-encapsulated muramyl tripeptide-phosphatidylethanolamine (L-MTP-PE) is a potent monocyte/macrophage activator. Sera from cats after intravenous L-MTP-PE administration showed TNFalpha activity using a WEHI-164 cell cytotoxicity assay and IL-6 activity using an IL-6 dependent mouse 7TD1 hybridoma cell proliferation assay. Serum TNFalpha activity peaked at 2 hours after L-MTP-PE administration. Significant differences from lipid-equivalent controls were observed at 2 and 3 hours (P <0.05). Neutralization of serum TNFalpha activity was accomplished with serial dilutions of rhTNFalpha monoclonal antibody. Serum IL-6 activity peaked at 3 hours after L-MTP-PE administration. Significant differences from lipid-equivalent controls were observed at 2, 3, and 4 hours (P <0.05). Neutralization of serum IL-6 activity was not achieved with goat anti-rhIL-6 polyclonal antibody. Intravenous L-MTP-PE, but not lipid-equivalent, induces serum TNFalpha and IL-6 activity in normal cats.

Fifty-five dogs with lymphoma were treated using a doxorubicin-based sequential combination chemotherapy protocol. Complete response, partial response, and no response were seen in 46, 4, and 5 dogs, respectively. The overall median remission duration and survival times were 36 and 51 weeks, respectively. Age, sex, weight, World Health Organization stage, World Health Organization substage (i.e., a = not ill, b = ill), serum calcium concentration, blood urea nitrogen concentration, breed and protocol alteration secondary to toxicity were evaluated for prognostic significance. Univariate analysis of prognostic factors identified sex, World Health Organization substage, and serum calcium as statistically significant (P < or = .05) variables for both survival and remission duration. Upon multivariate analysis, only substage (P = .036) was a significant prognostic factor for remission duration, whereas, both substage (P = .006) and sex (P = .005) were significant prognostic factors for survival.

L-asparaginase is an enzyme that inhibits protein synthesis by the depletion of sources of L-asparagine, which is necessary for transformed lymphoid cells to proliferate. L-asparaginase is used in the treatment of childhood acute lymphoblastic leukemia. A problem with L-asparaginase therapy is the immunogenicity of the enzyme and the development of anaphylactic reactions. Canine lymphoma is a predominantly B-cell tumor with widespread disease; without treatment, dogs with lymphoma usually survive 1-2 months. Canine lymphoma will respond to L-asparaginase therapy. A randomized double-blind study evaluated a polyethylene glycol (PEG) conjugate L-asparaginase combined with chemotherapy (vincristine, cyclophosphamide, doxorubicin, and prednisone). Thirty-five dogs were randomized to the PEG L-asparaginase group, and 34 dogs were randomized to the native L-asparaginase group. Thirty dogs (85.7%) achieved a complete remission (CR) with a median time to relapse of 217 days, and 32 (94.1%) dogs in the native L-asparaginase group achieved a CR with a median time to relapse of 214 days (P greater than 0.05). The asparaginase was well tolerated in both groups. Two dogs in the native L-asparaginase group had severe allergic reactions, and one dog in the PEG asparaginase group had a generalized urticarial reaction after repeated injections. This study indicates that PEG L-asparaginase has equal therapeutic efficacy to native L-asparaginase.

Dogs with mast cell tumors (MCT) are often affected with paraneoplastic syndromes such as gastrointestinal ulceration. The mechanism of ulceration is believed to be related to hyperhistaminemia. To test this hypothesis, plasma histamine and gastrin concentrations were measured in 17 dogs with MCT. Plasma histamine concentrations in dogs with MCT were significantly higher than those in normal dogs. Conversely, plasma gastrin concentrations in dogs with MCT were significantly lower than gastrin concentrations in normal dogs. Additionally, plasma gastrin concentrations were inversely related to plasma histamine concentrations, which provided indirect evidence for the presence of hyperacidity secondary to hyperhistaminemia (r2 = 57.7). Plasma histamine and plasma gastrin concentrations were not related to clinical stage of disease, tumor histologic grade, or tumor size. Median survival time was 245 days, with a range of 90 to 1315 days. Because the degree of hyperhistaminemia could not be predicted in this study from the clinical stage, histologic grade, or tumor size, these data suggest that hyperhistaminemia may occur in any dog with MCT.

Electron microscopy was used to diagnose primary ciliary dyskinesia in a litter of English pointer dogs and in a golden retriever dog. A technique of membrane solubilization, fixation, and negative staining with glutaraldehyde tannic acid identified abnormally constructed central and B microtubules in respiratory cilia from dogs with primary ciliary dyskinesia. Shortened outer dynein arms commonly associated with primary ciliary dyskinesia actually represents the absence of a specific subset of the three most peripheral components of the whole outer dynein arm structure.

Ethylene glycol-induced nephrotoxicosis was diagnosed in a dog with acute renal failure. Histologically, the dog had proximal tubular degeneration and necrosis, intraluminal calcium oxalate crystals, generally intact tubular basement membranes, and evidence of tubular regeneration. After 20 days of peritoneal dialysis and diuresis, renal function was adequate to maintain homeostasis without supportive care. Nine weeks after onset of the ethylene glycol-induced renal failure, the dog's kidneys were histologically and functionally normal.