Doxorubicin-induced cardiotoxicosis. Clinical features in 32 dogs.

Clinical cardiac abnormalities developed in 32 of 175 dogs that had various malignancies and were treated with doxorubicin: 31 dogs had electrocardiographic abnormalities including arrhythmias and nonspecific alterations in the R wave, ST segment, or QRS duration and 7 dogs had congestive heart failure. All seven dogs that had congestive heart failure died within 90 days. At necropsy, 13 of 32 affected dogs had noninflammatory myocardial degeneration, myocytolysis, vacuolation, and/or fibrosis and there was intramural coronary arteriosclerosis in all 13. Five dogs with lymphosarcoma were in complete clinical remission when they died of doxorubicin-induced cardiomyopathy, but the overall survival times of the lymphosarcoma subset was nevertheless longer than in previous studies. The clinical use of doxorubicin in the dog can cause cardiotoxicosis but the therapeutic benefit appears to outweigh risks in most dogs.

Prognostic factors in dogs with lymphoma and associated hypercalcemia.

Lymphoma and hypercalcemia were diagnosed in 37 dogs. Twenty-six of the dogs received chemotherapy. The association between some prognostic factors including clinical stage of disease, illness status, presence of bone marrow involvement, and presence of an anterior mediastinal mass and remission duration and survival time was evaluated. Statistical analysis of the prognostic factors showed that the presence of an anterior mediastinal mass had an adverse effect on remission duration (P less than 0.03). Calcium concentration was not significantly related to any of the prognostic factors evaluated. Dogs that received chemotherapy were more likely to be self-supporting than the dogs that were not treated (P less than 0.005). However, initial illness status was not significantly related to remission duration or survival time in the 26 dogs that were treated. Six dogs (25% of dogs treated) survived longer than 14 months. Five of these dogs were female. Overall mean and median remission times were 10.4 and 6 months, respectively.

Canine ehrlichiosis in six dogs with persistently increased antibody titers.

Chronic ehrlichiosis was diagnosed in six dogs on the basis of increased immunofluorescent antibody titers to Ehrlichia canis. Although clinical signs varied, all six dogs were anemic, hyperglobulinemic, and an IgG monoclonal gammopathy was documented in five dogs in which serum protein electrophoreses were performed. All dogs were treated with tetracycline for at least 14 days; four dogs also received immunosuppressive drugs. Clinical signs resolved within 1 week, hematologic abnormalities resolved in 1 to 5 months, and increased globulin concentrations normalized in 1 to 15 months; however, E. canis antibody titers remained increased for 15 to 31 months after initiation of treatment. Results of this study show that increased E. canis titers can persist in dogs with ehrlichiosis for many months after clinical recovery.

Etoposide (VP-16). Retrospective analysis of treatment in 13 dogs with lymphoma.

A retrospective analysis was performed of the effect of VP-16 (etoposide) in the treatment of 13 dogs with lymphoma. Twelve dogs had achieved partial (two) and complete (ten) responses to combination chemotherapy, but all were out of remission at the time of the trial. One dog had not previously had chemotherapy. There was minimal response to VP-16 chemotherapy in the 13 dogs studied, and only two of 13 dogs had some response to treatment. For one dog, complete and partial remission durations were one and three months, respectively. In another dog, there was partial remission of eight days. There were no responses in the other 11 dogs. The most serious adverse reaction after administration of VP-16 was an acute pruritic cutaneous reaction that occurred in 11 of the 13 dogs, which may have been associated with the vehicle of VP-16, polysorbate 80. Results showed that VP-16 has minimal activity for treatment of dogs with lymphoma that have experienced relapses after treatment with other anti-cancer drugs. More trials are needed with higher dosages and the oral form of the drug, which does not contain polysorbate 80.

Lymphomas in dogs. A morphologic, immunologic, and clinical study.

One hundred seventy-six canine lymphomas were classified morphologically using four of the major human lymphoma classification schemes (Rappaport, Lukes-Collins, Kiel, and the Working Formulation). All 176 dogs received the same chemotherapeutic protocol. Sixty-two of these lymphomas had their immunophenotypes established by examination of cell surface markers by automated cytofluorography. Several different morphologic types of canine lymphoma were identified and these were comparable to morphologic categories in human classification schemes. Follicular and low grade lymphomas were rare. The two most common morphologic types were diffuse large cell (centroblastic) and immunoblastic. The Kiel classification appeared to be the most useful human scheme for classifying the canine lymphomas. Cytofluorographic analysis was generally straightforward, and 60 of the 62 lymphomas were placed into one of three immunophenotypic categories: 27 pan-T(LQ1)+SIg+, 21 pan-T(LQ1)-SIg+, and 12 pan-T(LQ1)+SIg-. Two of the lymphomas could not be characterized immunologically because a pre-existing or reactive non-neoplastic population of lymphocytes made interpretation of single cell suspension analysis difficult. The authors identified correlations between morphology and survival and disease-free remission; dogs with high-grade tumors generally survived the longest and had the longest remissions. No correlations were identified between high concentrations of serum lactate dehydrogenase, age, sex, or stage of disease, and morphology, immunophenotype, remission, or survival times. A significant correlation between clinical illness and survival time was documented. The median age of the dogs was nine years, no significant effect of sex on prevalence was observed, and some breeds were significantly overrepresented. Significant morphologic-immunophenotypic correlations included shorter remission and survival times for T-cell tumors than B-cell tumors, and a highly significant correlation between the pan-T(LQ1)+SIg-"T cell" phenotype and hypercalcemia.

Treatment and prognostic factors in lymphoma in cats: 103 cases (1977-1981).

The records of 103 cats with lymphoma that underwent chemotherapy were reviewed. Diagnosis was confirmed by cytologic or histopathologic examination of appropriate tissue specimens. Sixty-four cats (62%) had a complete response to chemotherapy (median survival time, 7 months); 21 cats (20%) had a partial response (median survival time, 2.5 months); and 18 cats had a minimal response (median survival time, 1.5 months). Seventy-seven cats (75%) died of recurrent or progressive lymphoma, 9 cats died of feline leukemia-related anemia, 13 cats died of unrelated causes, and 4 cats were alive. Stage of disease was significantly (P = 0.009) related to response to treatment, and stage of disease and FeLV status were both significantly (P = 0.002 and P less than 0.001, respectively) related to survival.

Adenylate cyclase-stimulating, bone-resorbing and B TGF-like activities in canine apocrine cell adenocarcinoma of the anal sac.

Canine apocrine cell adenocarcinoma of the anal sac (APO-AS) is a spontaneously occurring tumor that causes humorally mediated hypercalcemia in 90% of cases. To further define the nature of the responsible mediator in APO-AS, we examined tumor extracts from five APO-AS and four control tumors for adenylate cyclase-stimulating activity (ACSA). All extracts from APO-AS contained potent ACSA, whereas the four control tumors did not. The ACSA extracted from one tumor demonstrated a dose response curve parallel to that of synthetic bovinePTH-(1-34) and was 80% inhibited by Nle8,18,Tyr34 bPTH-(3-34)amide at a concentration of 10(-5) M. Extracts from three APO-AS and three control tumors were also examined for in vitro bone-resorbing activity (BRA). All APO-AS contained significant BRA, stimulating resorption 1.47 to 2.13-fold over basal, whereas none of the control tumors stimulated resorption. Purification of one extract using C18 reverse-phase high pressure liquid chromatography (RP-HPLC) resulted in a single sharp peak of ACSA which was 400-fold purified compared with the initial extract. This pool also contained significant bone-resorbing activity, whereas none of the adjacent pools did. Purification of a second extract using sequential CN and C18 RP-HPLC followed by size exclusion HPLC resulted in material that was at least 10,000-fold purified, and showed co-purification of ACSA and B TGF-like activity.

Canine osteosarcoma. Treatment by amputation versus amputation and adjuvant chemotherapy using doxorubicin and cisplatin.

Osteosarcoma was diagnosed in 38 dogs. Thirty-six tumors originated from the appendicular skeleton and two from the axial skeleton. Nineteen of the dogs were treated with amputation alone, and 19 were treated with amputation and adjuvant chemotherapy consisting of doxorubicin and cisplatin. The 36 dogs with appendicular osteosarcoma had complete amputation of the affected limb, whereas the two dogs with osteosarcoma of the axial skeleton had an en bloc resection. The mean survival of the 19 dogs treated with amputation alone was 218 days (median, 175 days). Ten dogs were alive at 6 months and four survived 1 year. None of the dogs survived longer than 16 months. Radiographic lesions consistent with metastatic osteosarcoma were seen after surgery in the nine dogs in which radiographs were taken. The mean survival of the 19 dogs treated with amputation and chemotherapy was 415 days (median, 300 days). Drug toxicity was not observed. Fifteen dogs were alive at 6 months, seven dogs were alive at 1 year, 5 dogs were alive at 2 years, and two dogs were alive at 3 years or longer. One dog is alive and well at 25 months. Radiographic lesions suggestive of metastatic osteosarcoma developed in the other 18 dogs. The 19 dogs treated with amputation and chemotherapy had significantly longer survival times than the dogs treated with amputation alone.

Chemotherapy versus chemotherapy plus radiotherapy in the treatment of tonsillar squamous cell carcinoma in the dog.

The effect of adjuvant chemotherapy and combined chemotherapy and radiotherapy in 22 dogs with advanced canine tonsillar carcinoma (World Health Organization [WHO], T2-3 primary tumor with infiltration into surrounding tissues) was evaluated. There were four treatment groups of at least five dogs each. Combinations of chemotherapeutic drugs reported to have activity against squamous cell carcinoma in humans and dogs (doxorubicin, cisplatin, vinblastine, and cyclophosphamide) were administered after tonsillectomy. Radiation therapy (orthovoltage type, external beam) was combined with chemotherapy in one treatment group. The dogs that had combination radiation therapy and chemotherapy had higher response rates and significantly longer survival times. However, most dogs died of progression of disease.

Efficacy and toxicity of doxorubicin and cyclophosphamide used in the treatment of selected malignant tumors in 23 cats.

Twenty-three cats with malignant, nonhematopoietic tumors were treated with doxorubicin and cyclophosphamide. Fourteen cats had nonresectable tumors of the mammary gland, and nine had tumors of the oral cavity. Of the cats with mammary gland adenocarcinoma, seven cats had a partial response to treatment and seven cats had no response. Of the cats with oral tumors, one cat had a complete response, three cats had a partial response, and five cats had no response. All 23 cats are dead because of tumor progression or recurrence. Toxic effects were seen in 18 of the cats; most were transient and required no alteration in the treatment protocol. A high response rate combined with acceptable toxicity warrants further evaluation of combination doxorubicin and cyclophosphamide chemotherapy in cats with nonhematopoietic neoplasia.

Humoral hypercalcemia of malignancy in canine lymphosarcoma.

Studies on the pathogenesis of hypercalcemia in canine lymphosarcoma have led to conflicting results. The biochemical and bone histomorphometric findings in canine lymphosarcoma were examined in 19 hypercalcemic and 17 nonhypercalcemic dogs with lymphosarcoma. Compared to the nonhypercalcemic group, the hypercalcemic dogs demonstrated an increase in fasting and 24-h calcium excretion, an increase in fractional phosphorus excretion, and a significant increase in nephrogenous AMP excretion. Plasma 1,25-dihydroxyvitamin D and immunoreactive PTH levels were equivalent in the two groups. Quantitative bone histomorphometry performed on iliac crest biopsies revealed increased parameters of bone resorption in those hypercalcemic dogs with no evidence of tumor at the biopsy site, without a compensatory increase in bone formation. Acid-urea tumor tissue extracts from eight hypercalcemic and six nonhypercalcemic dogs were examined for adenylate cyclase-stimulating activity (ACSA). All tumors from hypercalcemic dogs contained ACSA, whereas none of the tumors from nonhypercalcemic dogs had ACSA. Further purification of one tumor extract yielded an adenylate cyclase-stimulating protein which appeared to interact specifically with the PTH receptor. We conclude that in some cases, hypercalcemia in canine lymphosarcoma is mediated by a tumor-derived circulating bone-resorbing factor which is distinct from PTH. ACSA detected in tumor tissue appears to be a reliable marker for the syndrome in vivo. The role of this activity in the pathogenesis of the syndrome remains to be determined.

Renal lymphoma in cats: 28 cases (1977-1984).

Renal lymphoma was diagnosed, staged, and treated in 28 cats. Renal lymphoma staging was done according to clinical findings: 11 cats had stage-2 lymphomas, 5 had stage-3 lymphomas, 6 had stage-4 lymphomas, and 6 had stage-5 lymphomas. All cats were treated with chemotherapy: 17 cats had a complete response, 9 cats had a partial response, and 2 cats had no response. The cats with stage-2 lymphomas that were FeLV-test negative had the best response to treatment.

Use of splenectomy in the management of lymphoma in dogs: 16 cases (1976-1985).

Sixteen dogs with lymphoma underwent splenectomy to relieve signs of massive splenomegaly including splenic rupture. The most common preoperative hematologic abnormalities, anemia and thrombocytopenia, were reversed in all dogs surviving the initial postoperative period. Within 6 weeks after surgery, 5 dogs died because of disseminated intravascular coagulation and sepsis. The remaining 11 dogs underwent chemotherapy. These 11 dogs had a complete response rate of 66% at one month after surgery; the mean and median survival times were 9.3 and 5 months, respectively. In 7 dogs evaluated until death, the mean and median survival times were 13.4 months and 14 months, respectively.

Use of plasmapheresis and chemotherapy for treatment of monoclonal gammopathy associated with Ehrlichia canis infection in a dog.

Monoclonal gammopathy associated with Ehrlichia canis infection was diagnosed in a German Shepherd Dog. The dog was treated by use of chemotherapy and tetracycline and by plasmapheresis. The dog tolerated plasmapheresis and long-term drug therapy well, and clinical signs resolved over a 90-day period. The monoclonal gammopathy resolved after treatment, but specific antibody to E canis indicated suppression followed by a rebound to the initial high titer.

Evaluation of some prognostic factors for advanced multicentric lymphosarcoma in the dog: 147 cases (1978-1981).

A total of 147 dogs treated with a combination of chemotherapy procedure (vincristine, L-asparaginase, cyclophosphamide, and methotrexate) were evaluated for response to therapy and the influence of age, sex, clinical stage, and body weight to duration of response. Complete response was achieved in 113 dogs (77%), partial response in 26 dogs (17.7%), and no response in 8 dogs (5.4%). The median survival time for the dogs with complete and partial responses was 265 days. An analysis of factors associated with prognosis revealed that age, clinical stage, and body weight were not associated with response to therapy, whereas sex was. Females had a significantly prolonged remission and survival time (P = 0.0001).

Chronic lymphocytic leukemia in the dog: 22 cases (1974-1984).

Chronic lymphocytic leukemia was diagnosed in 22 dogs. Diagnosis was based primarily on detection of lymphocytosis and bone marrow infiltration with small lymphocytes similar to those seen in the blood. More than 50% of the dogs had monoclonal gammopathy, and, of these, 40% had monoclonal light-chain (Bence Jones) proteinuria. Hyperviscosity syndrome was observed occasionally. Most dogs were treated with chemotherapy. For the 17 dogs treated greater than or equal to 30 days, the survival times ranged from 30 to 1,000 days.

Prognostic factors for multiple myeloma in the dog.

Multiple myeloma was diagnosed in 60 dogs. Diagnosis was confirmed in each case by observation of greater than 5% plasma cells on examination of a bone marrow aspirate and detection of monoclonal gammopathy of immunoglobulin (Ig) A or IgG. Treatment with melphalan, cyclophosphamide, and prednisone was associated with long-term survival (median, 540 days). Response to therapy was significantly related to prognosis (P less than 0.01), whereas hypercalcemia and Ig light chain proteinuria (Bence Jones) were associated with shorter median survival times.

Uric acid and phosphorus excretion in dogs with lymphosarcoma.

Serum uric acid and phosphorus concentrations were determined for 27 dogs with multicentric lymphosarcoma before and after chemotherapy. Mean serum uric acid values in dogs before treatment were significantly higher (P less than 0.05) than those of a control group of healthy dogs. Serum uric acid values did not change after treatment. Of the 27 dogs, 13 had 24-hour urine collections to determine endogenous creatinine clearance and quantitation of uric acid and phosphorus excretion before and after treatment for lymphosarcoma. Mean values for 24-hour creatinine clearance before and after treatment were statistically similar in dogs with lymphosarcoma, although the values were lower than those in a normal range. Total urinary phosphorus excretions were increased significantly (P less than 0.01) after treatment without change in fractional excretion. Chemotherapeutic agents used accounted for the significant (P less than 0.05) increase in urine volume after treatment and may have affected the excretion of uric acid and phosphorus. Seemingly, dogs with uncomplicated lymphosarcoma rarely have renal dysfunction or clinically important alterations in uric acid or phosphorus excretion secondary to rapid tumor lysis. However, preexisting renal disease or systemic complications, such as hypercalcemia, may be associated with increased risk of further renal impairment during treatment.