Phase I evaluation of CCNU (lomustine) in tumor-bearing cats.

1-(2-Chloroethyl)3-cyclohexyl-1-nitrosourea (CCNU) is an alkylating agent in the nitrosourea subclass. A prospective evaluation of CCNU was done to determine the maximally tolerated dosage of CCNU in tumor-bearing cats. Response data were obtained when available. Twenty-five cats were treated with CCNU at a dosage of 50-60 mg/m3 body surface area. Complete hematologic data were available for 13 cats. Neutropenia was the acute dose-limiting toxicity. The median neutrophil count at the nadir was 1,000 cells/microL (mean, 2,433 cells/microL; range, 0-9,694 cells/microL). The time of neutrophil nadir was variable, occurring 7-28 days after treatment, and counts sometimes did not return to normal for up to 14 days after the nadir. Based on these findings, a 6-week dosing interval and weekly hematologic monitoring after the 1st treatment with CCNU are recommended. The nadir of the platelet count may occur 14-21 days after treatment. The median platelet count at the nadir was 43,500 cells/microL. No gastrointestinal, renal, or hepatic toxicities were observed after a single CCNU treatment, and additional studies to evaluate the potential for cumulative toxicity should be performed. Five cats with lymphoma and 1 cat with mast cell tumor had measurable responses to CCNU. Phase II studies to evaluate antitumor activity should be completed with a dosing regimen of 50-60 mg/m3 every 6 weeks.

Scintigraphic assessment of gastric emptying of canned and dry diets in healthy cats.

OBJECTIVE: To characterize factors that affect solid-phase gastric emptying in healthy cats by use of nuclear scintigraphy and to assess differences in emptying patterns of dry and canned diets. ANIMALS: 20 healthy cats. PROCEDURE: 2 groups of 10 cats each were fed dry or canned diet for at least 2 weeks before scintigraphy was done. Diets were labeled with 99mTc-disofenin. After ingestion of labeled meals, scintigraphic images were obtained at 0, 15, 30, 45, and 60 minutes, then every 30 minutes to 6 hours. Gastric emptying scans were obtained 3 times for each cat for each diet, in a complete crossover design. The T90, T50, and T20 (times when 90, 50, and 20% of initial meal activity remained in the stomach, respectively) were derived from gastric emptying curves fit to nonlinear models. A mixed models approach was used for data analysis. RESULTS: Gastric emptying was well described by a nonlinear model. Meal size, water intake, and diet type significantly (P < 0.05) effected gastric emptying. The T90, T50, and T20 increased with meal size, regardless of diet type or water intake. Gastric emptying of a dry diet meal took significantly (P < 0.05) longer than that of an isocaloric meal of canned diet, except when meal size was small. Differences in gastric emptying of dry and canned diets varied with the phase (T90 vs T50 vs T20) of emptying. CONCLUSION: Water intake, meal size, and diet type significantly influence gastric emptying in healthy cats, and these factors must be considered in analysis of gastric emptying data.

Immunohistochemistry of pancreatic islet cell tumors in the ferret (Mustela putorius furo).

Twenty-two pancreatic islet cell tumors and normal pancreatic islets from ferrets were evaluated by immunohistochemistry for expression of the peptide hormones insulin, somatostatin, glucagon, and pancreatic polypeptide (PP) and the neuroendocrine markers chromogranin A (CgA) and neuron-specific enolase (NSE). In normal pancreatic islets, the majority of cells stained strongly with CgA and NSE. A cells, B cells, D cells, and PP cells stained strongly with glucagon, insulin, somatostatin, and PP, respectively. All 22 tumors stained with CgA and NSE. The proportion of cells within tumors staining for CgA was variable, but more than half of the cells stained positively in 18 of the tumors. The intensity of staining for CgA was strongly (reactivity equivalent to or greater than normal islet cells in adjacent tissue) in 11 moderate in six, and weak in five of the tumors. All tumors stained for NSE, with > or = 50% of the cells staining in 21 of the tumors, and the intensity of staining was strong in 18 of the tumors. Twenty of 22 tumors stained positively for insulin. with > or = 50% of the cells staining in 19 of them. The intensity of staining for insulin was strong in 12, moderate in seven, and weak in one of the tumors. Approximately < or = 1% of the cells in 15 of 22 tumors stained for somatostatin, five tumors stained for pancreatic polypeptide, and three tumors stained for glucagon. These data indicate that the majority of islet cell tumors of ferrets express immunohistochemically detectable insulin. CgA and NSE are both useful general markers for such tumors, including those that are insulin negatives. Commercially available antisera to CgA, NSE, insulin, glucagon, somatostatin, and PP work well in formalin-fixed, paraffin-embedded tissue for immunophenotyping islet cell tumors in the ferret.

Chromogranin A plasma concentration and expression in pancreatic islet cell tumors of dogs and cats.

OBJECTIVES: To describe expression of the neuroendocrine marker chromogranin A (CgA) in canine and feline pancreatic islet cell tumors and their metastases, and to evaluate plasma CgA concentration in dogs and cats with insulinoma. SAMPLE POPULATION: Paraffin-embedded tissues from 25 canine and 2 feline pancreatic islet cell tumors, 5 canine and 6 feline exocrine pancreatic tumors, and normal pancreatic tissue from 2 dogs and 2 cats. Heparinized plasma samples from 3 dogs and 2 cats diagnosed with insulinoma, and 10 control plasma samples from each species. PROCEDURE: Immunohistochemical analysis was performed on the 42 tissue specimens, using antisera against CgA, neuron-specific enolase, insulin, somatostatin, glucagon, and pancreatic polypeptide. The 25 plasma samples were evaluated, using a soluble-phase, double-antibody, equilibrium radioimmunoassay directed against the amino- and carboxy-terminal peptides of bovine CgA. RESULTS: Chromogranin A expression was found in 76% of canine and 2 of 2 feline pancreatic islet cell tumors. Of 7 animals with CgA immunoreactivity in primary tumors, 6 also had CgA immunostaining of metastatic lesions. Plasma CgA concentration in 2 dogs with insulinoma (0.9, 1.0 ng/ml) exceeded the reference range established for 10 clinically normal control dogs (0.50 +/- 0.16 ng/ml). Feline plasma CgA samples had extensive nonspecific background immunoreactivity. CONCLUSIONS: Chromogranin A is a useful immunohistochemical marker for pancreatic tumors of neuroendocrine origin and their metastases. Plasma CgA concentration determined by radioimmunoassay was high in 2 dogs with insulinoma. CLINICAL RELEVANCE: Immunohistochemical staining of tissues or cytologic specimens for CgA and/or neuron-specific enolase may help distinguish masses of unknown origin as neuroendocrine in nature. Increase in plasma CgA concentration may be useful diagnostically for animals with suspected neuroendocrine tumors.

Adrenal incidentalomas. Diagnostic workup of the incidentally discovered adrenal mass.

The incidentally discovered adrenal mass is a diagnostic dilemma veterinarians are likely to face with increasing frequency in the coming years. Dogs and cats may be more prone to functional adrenal lesions than are humans. Most adrenal tumors are benign, but a significant number of adrenocortical carcinomas (approximately 12%) and metastatic lesions within the adrenal glands (3% to 34%) do occur. Evaluation for hypertension, hypokalemia, and loss of hypothalamic-pituitary-adrenal responsiveness to a low dose of dexamethasone is appropriate for all patients with adrenal incidentalomas. The value of clinical and historical signs of hormonal overexpression should not be underestimated. More invasive or expensive diagnostic testing should be predicted on suspicions raised by the history and clinical signs. New diagnostic clinicopathologic tests, including plasma CgA and serum DHEAS, should be investigated in veterinary patients. Advanced diagnostic imaging using nuclear scintigraphy and chemical-shift MRI may offer veterinarians sensitive and specific noninvasive tools to consider for the evaluation of these patients. Patients with large masses, tumors with signs of malignancy, or productive adrenal tumors (plus or minus cortisol-producing tumors in which chemical ablation with mitotane can be attempted) should be considered candidates for exploratory surgery.

Evaluation of a multidrug chemotherapy protocol (ACOPA II) in dogs with lymphoma.

A chemotherapeutic protocol using cyclophosphamide, vincristine, prednisone, doxorubicin, and L-asparaginase (ACOPA II) was evaluated in dogs with lymphoma. The response rate for 68 dogs treated with ACOPA II (complete remission [CR] 65%, partial remission [PR] 10%) was lower than that for 41 dogs treated with a related protocol previously evaluated (ACOPA I; CR 76%, PR 12%). Initial treatment with doxorubicin and prednisone did not decrease the prevalence or severity of toxicity during induction. The mortality during induction was 22%. The median duration of CR for dogs treated with ACOPA II was 9 months, with 40% still in remission at 1 year and 21% at 2 years. The rate of CR was lower for dogs with signs of illness at presentation (substage b) and for dogs weighing less than 15 kg. Age was negatively correlated with survival time and duration of remission. Dogs with immunoblastic lymphoma had a more favorable prognosis than did those with lymphoblastic lymphoma. Survival times were also longer for dogs in substage a at presentation. Seven dogs in which treatment was discontinued while in remission had comparable remission duration to that achieved by dogs receiving long-term maintenance chemotherapy.

Chylothorax and chylous ascites in a dog with mediastinal lymphangiosarcoma.

A 10-year-old, male toy poodle presented for evaluation of a progressively worsening, harsh, nonproductive cough. Chylous pleural effusion, lymphopenia, thrombocytopenia, normoblastemia, and recurrent subcutaneous bruising were diagnosed. Surgical exploration of the cranial mediastinum revealed extensive, redundant connective tissue which was confirmed by histopathology to be mediastinal lymphangiosarcoma (LAS). During surgical placement of a fenestrated silastic mesh for passive pleuroperitoneal drainage, chylous ascites also was diagnosed. The patient was euthanized two days postoperatively due to persistent chylothorax. The etiopathogenesis of chylothorax and chylous ascites are discussed. Previous case reports of lymphatic endothelial neoplasia are reviewed.

cGMP stimulates bile acid-independent bile formation and biliary bicarbonate excretion.

The effect of guanosine 3',5'-cyclic monophosphate (cGMP) on hepatic bile formation was studied in isolated perfused rat livers and rat hepatocytes. Studies in isolated perfused rat livers showed that infusion of 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP, 3 micromol/min or 100 microM) 1) increased bile flow without affecting biliary excretion of simultaneously infused taurocholate, 2) increased biliary concentration and excretion of HCO3(-) but did not affect biliary excretion of glutathione, and 3) increased net perfusate H+ efflux without affecting hepatic O2 uptake. Studies in isolated rat hepatocytes showed that 1) 8-BrcGMP increased intracellular pH in the presence (but not in the absence) of extracellular HCO-3, and effect inhibited by 4,4' -diisothiocyanostilbene-2,2'-disulfonic acid and Na+ replacement, 2) 8-BrcGMP did not affect taurocholate uptake and intracellular [Ca2+], and 3) bile acids, like ursodeoxycholate and cholate, did not increase cellular cGMP. Taken together, these results indicate that cGMP stimulates bile acid-independent bile formation, in part by stimulating biliary HCO3- excretion. cGMP may increase HCO3- excretion by stimulating sinusoidal Na+ - HCO3- cotransport, but not Na+/H+ exchange. cGMP, unlike adenosine 3',5'-cyclic monophosphate, may not regulate hepatic taurocholate transport, and bile acid-induced HCO3- rich choleresis may not be mediated via cGMP.