Spontaneous acute tumor lysis syndrome as a cause of early deaths in short-term carcinogenicity studies using p53 +/- mice.

Acute tumor lysis syndrome (ATLS) is a potentially lethal condition precipitated by the massive release of intracellular components such as nucleic acids, potassium, and phosphorus, following a rapid and widespread lysis of tumor cells. Herein, the authors describe the high incidence and characteristic histopathologic lesions of acute ATLS in p53-deficient mice used in 2 short-term carcinogenicity studies. ATLS was a frequent cause of early death in p53 (+/-) mice in these studies and was consistently associated with the presence of disseminated lymphoma and leukemia. Although a heavy tumor burden and leukemia were present in all affected mice, the absence of ATLS in other mice with equally severe lymphoma and leukemia indicates that these tumor burdens are necessary but insufficient to cause ATLS in mice. The hallmark histopathologic findings of ATLS in mice are the disseminated microemboli composed of nuclear and cytoplasmic debris derived from lysed tumor cells. The mechanical obstruction of capillary beds by these microemboli appeared to be the proximate cause of the early deaths of mice in these studies. Microemboli may contribute to the pathogenesis of acute renal failure and other clinical signs associated with ATLS in other species. Recognition of ATLS in laboratory animals is critical in studies intended to evaluate the efficacy and/or toxicity of anticancer treatments, where early deaths due to ATLS might otherwise be attributed to test article toxicity. Further studies on the role of microemboli in the pathogenesis of ATLS may elucidate pathogenetic mechanisms and lead to improved approaches to clinical management and treatment of this potentially lethal condition.

Chronic toxicity/oncogenicity evaluation of 60 Hz (power frequency) magnetic fields in B6C3F1 mice.

A 2-yr whole-body exposure study was conducted to evaluate the chronic toxicity and possible oncogenicity of 60 Hz (power frequency) magnetic fields in mice. Groups of 100 male and 100 female B6C3F1 mice were exposed to pure, linearly polarized, transient-free 60 Hz magnetic fields at flux densities of 0 Gauss (G) (sham control), 20 milligauss (mG), 2 G, and 10 G; an additional group of 100 male and 100 female B6C3F1 mice received intermittent (1 hr on/1 hr off) exposure to 10 G fields. A small but statistically significant increase in mortality was observed in male mice exposed continuously to 10 G fields; mortality patterns in all other groups of mice exposed to magnetic fields were comparable to those found in sex-matched sham controls. Body weight gains and the total incidence and number of malignant and benign tumors were similar in all groups. Magnetic field exposure did not increase the incidence of neoplasia in any organ, including those sites (leukemia, breast cancer, and brain cancer) that have been identified in epidemiology studies as possible targets of magnetic field action. A statistically significant decrease in the incidence of malignant lymphoma was observed in female mice exposed continuously to 10 G fields, and statistically significant decreases in the incidence of lung tumors were seen in both sexes exposed continuously to 2 G fields. These data do not support the hypothesis that chronic exposure to pure, linearly polarized 60 Hz magnetic fields is a significant risk factor for neoplastic development in mice.

Assessment of the histopathological lesions and chemical analysis of feral cats to the smoke from the Kuwait oil fires.

Twenty-six adult or subadult feral cats were collected from Kuwait approximately 8 months after the ignition of the Kuwait oil wells. These animals were obtained from two sources: 12 animals from Kuwait City, a relatively smoke-free area, and 14 from the city of Ahmadi, an area with heavy smoke. Animals were euthanized and a complete set of tissues consisting of all major organs was taken for histopathology. Samples of lung, liver, kidney, urine, and blood were also taken for toxicology. Histopathological lesions observed in the lung were mild accumulations of anthracotic pigment in the lungs of 17 cats. Hyperplasia of the bronchial and bronchiolar gland in 8 cats, and smooth muscle hyperplasia of bronchioles in 14 cats. Tracheal gland hyperplasia was observed in 7 cats, and minimal squamous metaplasia of the tracheal mucosa in 17 cats, Laryngeal lesions consisted of submucosal gland hyperplasia in 2 cats and squamous metaplasia of the mucosa in 5 cats. Hyperplasia of the nasal submucosal glands was observed in 6 animals. The pharyngeal mucosa as well as other organs and organ systems were normal in all cats. Atomic absorption analysis for 11 metals was performed; vanadium and nickel levels (two metals that were present in the smoke from the oil fires) are not indicative of substantial exposure to the oil fires. Based on the histopathological findings and toxicological analysis, it is felt that inhalation of air contaminated with smoke from the oil fires had little or no long-term effect on the animals examined.

Histopathologic lesions in sea otters exposed to crude oil.

Following the Exxon Valdez oil spill in Prince William Sound, Alaska, sea otters (Enhydra lutris) that appeared to be contaminated with oil, that were in danger of becoming contaminated, or that were behaving abnormally were captured and taken to rehabilitation centers. Exposure to oil was assessed by visual examination when otters arrived at the centers. Degree of oil exposure was graded according to the following criteria: oil covering greater than 60% of the body--heavily contaminated; oil covering 30-60% of the body--moderately contaminated; oil covering less than 30% of the body or light sheen on fur--lightly contaminated. If there was no oil visible, otters were considered uncontaminated. Tissues from 51 oil-contaminated sea otters (14 males, 37 females) and from six uncontaminated sea otters (three males, three females) that died in rehabilitation centers were examined histologically. Among oil-contaminated sea otters, 19/46 had interstitial pulmonary emphysema, 13/40 had gastric erosion and hemorrhage, 11/47 had centrilobular hepatic necrosis, 14/47 had periportal to diffuse hepatic lipidosis, and 10/42 had renal tubular lipidosis. Of the uncontaminated sea otters, 1/6 had gastric erosion and hemorrhage and 1/6 had diffuse hepatic lipidosis. Histologic examinations were performed on tissues from five sea otters (three males, two females) found dead with external oil present 15 to 16 days after the spill. Periportal hepatic lipidosis and renal tubular lipidosis were found in 3/5, and interstitial pulmonary emphysema was found in 1/5. Tissues from six apparently normal sea otters (four males, two females) collected from an area not affected by an oil spill were examined histologically, and none of these lesions were found. We conclude that interstitial pulmonary emphysema, centrilobular hepatic necrosis, and hepatic and renal lipidosis of sea otters were associated with exposure to crude oil. Gastric erosion and hemorrhage may have been associated with stress of captivity and/or oil exposure.

Pancreatic polypeptide and insulin-secreting tumor in a dog with duodenal ulcers and hypertrophic gastritis.

A 7-year-old spayed female Cocker Spaniel was hospitalized with a history of chronic vomiting, anorexia, and weight loss. Laboratory abnormalities included leukocytosis, metabolic alkalosis, hypoglycemia, hypoproteinemia, and hyperinsulinemia. Gastroscopy and ultrasonography revealed multiple gastric masses and a possible pancreatic mass, respectively. Examination of tissues obtained at necropsy showed a pancreatic adenocarcinoma with hepatic metastasis, gastric hypertrophy, and multiple duodenal ulcers. Immunocytochemical staining of the neoplasia was positive for pancreatic polypeptide (PP) and insulin and negative for gastrin, calcitonin, adrenocorticotropic hormone (ACTH), serotonin, L-enkephalin, chromagranin, glucagon, and somatostatin. Subsequent serum gastrin and PP assays showed a fasting hypergastrinemia with a normal response of gastrin to provocative testing and extremely increased PP values. The high PP values may have resulted in the vomiting and gastrointestinal ulceration. A PP-secreting tumor has not previously been reported in the dog.

Hepatic lesions associated with Cooperioides hepaticae (Nematoda: Trichostrongyloidea) infection in impala (Aepyceros melampus) of the Kruger National Park.

Intrahepatic biliary lesions were observed in two of 12 lambs, seven of 12 yearlings and 10 of 25 adult impala (Aepyceros melampus) surveyed in the Kruger National Park, Republic of South Africa. Lesions were associated with the nematode Cooperioides hepaticae, a trichostrongyloid parasite that inhabits the bile ducts of impala, and ranged from a mild chronic-eosinophilic cholangitis to foci of florid hyperplastic cholangitis with duct ectasia. The latter almost always contained viable worms and, after the worms died, the lesions appeared as foreign-body granulomas. Infection was acquired early in life; severe lesions were seen most frequently in yearlings. Adults were less severely infected, which suggested an acquired immunity. Although the incidence of infection was high, cooperiiasis did not appear to be a serious herd-health problem at the time of this study.

A mycobacteriosis in a sheep resembling paratuberculosis (Johne's disease).

In a sheep which was euthanased because of severe emaciation and weakness, slight thickening of the ileum was seen grossly. Microscopically there was a granulomatous ileitis with obliterative lymphangitis and lymphangiectasis. Granulomatous lesions were also present in the liver and some mesenteric lymph nodes. Large numbers of acid-fast bacilli were present within epithelioid macrophages in the lamina propria of the ileum. Although the identity of the Mycobacterium spp. involved was not established, the possibility of paratuberculosis is discussed. The apparent rarity of this disease in sheep in South Africa is considered. Particular attention is drawn to the absence of diarrhoea in this case, to the slightness of the gross changes and to the importance of submitting material for mycobacterial culture.

Orbital chondroma rodens in a dog.

A chondroma rodens involving the superficial medial aspect of the right orbit was diagnosed in a 9-year-old dog referred because of chronic unilateral epiphora. Examination revealed several ophthalmic abnormalities attributable to a space-occupying mass in the superficial medial aspect of the orbit. The mass was excised; however, regrowths at the primary site necessitated additional surgical interventions. The dog was given radiation therapy, which provided encouraging results. Subtle histologic differences as well as differing epidemiologic features suggest that chondroma rodens is not analogous to the human entity of juvenile aponeurotic fibroma, to which it has been compared in the past.