The problem of latency in the development of tumors following exposure to nickel compounds.

Six previously published animal studies of tumor production have been reviewed, in order to relate time interval between exposure to nickel and development of tumor formation. Biopsies at intervals before final tumor formation, in some of these experiments, were reviewed to define interim changes between exposure and tumor diagnosis. Correlation between rat and human life span was used to suggest a latency of human tumor expectancy following exposure to nickel.

Fat embolism to the cardiac conduction system associated with sudden death.

During a brief hospital stay, a patient under treatment with corticosteroids for lymphoma died suddenly and unexpectedly. At autopsy, fat emboli were identified in the lungs, myocardium, liver, and brain. Examination of the cardiac conduction system revealed fat emboli in the vessels of the bundle of His as well as those accompanying the bundle branches, a finding believed to have resulted in the sudden death. This report is the first of fat embolization to the cardiac conduction system and emphasizes the importance of examination of this system in cases of unexplained or sudden death.

Histogenesis of subcutaneous malignant tumors resulting from nickel subsulfide implantation.

Tumors are described which have been produced by subcutaneous (s.c.) implantation of nickel subsulfide (Ni3S2) in 00 gelatin capsules in the left axillary region of Fischer 344 rats. This is in contradistinction to previous accounts where intramuscular (i.m.) or, in a few cases, subcapsular testicular implantation sites have been used. The advantages of the s.c. route are discussed, including the removal of the difficulties of distinguishing degenerating and regenerating striated muscle cells from tumor cells. The s.c. induced tumors were transplanted as far as the F6 generation, in some cases. Cells from tumor transplanted as far as the F3 generation were grown in tissue culture and then reimplanted s.c. Cytology of the tumors remained remarkably constant in all tumors, even after serial transplants and culture. A characteristic storiform pattern, with two major cell types -myofibroblasts and histiocyte-like cells, was seen. The question of pluripotential cell origin is discussed. The striking similarity of appearance to human malignant fibrous histiocytoma is noted; however, in view of the somewhat controversial origin of the human tumor, the simple designation, "nickel-induced malignant tumor of pluripotential origin", is preferred. The use of this model with its demonstrated ability to reproduce characteristic appearances seems to be valuable for the study of soft tissue sarcomas.

Nickel-induced malignant tumors.

A series of malignant tumors experimentally induced by implanting Ni3S2 in gelatin capsules into the right hind limb of Fischer 344 rats is described. In this series, histology and ultrastructure revealed two major cell types. These are described as fibroblast-like and histiocyte-like. In addition, numerous giant cells, including large bizarre multinucleate giant cells with granular cytoplasm, were also seen. In this preliminary report, no more precise diagnosis will be given for this tumor than "malignant tumor of pluripotential origin". Further work is proposed to define more specifically its histogenesis. The appearances of the experimentally produced tumor are compared with certain tumors found in humans and also in experimentally induced tumors by Maruyama et al designated as malignant fibrous histiocytoma (MFH).

The pathologic response of the liver and thyroid of the rat to potassium prorenoate (SC-23992).

A 3-month dose range finding study in preparation for a 2-yr carcinogenicity study of potassium prorenoate (SC-23992), a steroid with an antihypertensive profile, is reported. The drug was administered by gavage once daily at doses of 10, 30, and 100 mg/kg/day to Charles River CD rats. Treatment was terminated at 13 weeks and 10 randomly selected animals from each treatment group were killed and necropsied. The remaining 10 animals in each dose group, including controls, were maintained for an additional 4 weeks, in order to investigate reversibility of changes, and then were killed and necropsied. Dose-related increases in thyroid-stimulating hormone (TSH) levels were observed in treated animals of both sexes during the dosing period and the changes were statistically significant and correlated with an increased thyroid weight in females at 13 weeks. Dose-related morphologic changes in the thyroid, observed by light and electron microscopy, were compatible with the effects of TSH stimulation. Liver weights, which increased, were dose-related. In females the increase was statistically significant at the high dose at 2, 4, and 13 weeks. In males it was significant at the high dose at 13 weeks. Microsomal enzyme levels were increased in a time- and dose-related manner with higher values in females than in males. The pattern of enzyme induction was of the type exemplified by pregnenolone- 16-alpha-carbonitrile. Morphologic changes in the liver showed centrilobular hepatocyte enlargement with smooth endoplasmic reticulum membrane proliferation confirmed by electron microscopy. All positive findings returned to normal after the 4-week treatment-free period. The relationship between the thyroid stimulation to liver enzyme induction is of interest. Evidence is presented here that in the presence of SC-23992, TSH stimulation and liver enzyme induction occurred. The possibility that the liver metabolism stimulates the thyroid T3, T4 elimination with secondary TSH activity is a possible explanation, but on the basis of existing information, direct action by SC-23992 on the thyroid cannot be excluded.

Oesophagostomiasis in feral monkeys (Macaca mulatta).

For periods of 3, 6, and 12 months, 104 feral rhesus monkeys (Macaca mulatta) were on test. At the time of necropsy, 26 had caseous granulomatous lesions in the submucosa of the colon consistent with oesophagostomiasis. Five also had histologically identified granulomatous lesions without caseation of various colonic and more distant arterioles. The lesions were seen in the submucosa and subserosa of the colon, the kidney, the adventitial tissue of the prostate, the pancreas, and the heart. Presumptive evidence of the migration of the parasite was found in the adventitial tissue of the esophagus. Fragments of the larvae in arterioles and the caseous submucosa of the colon were consistent morphologically with the species Oesophagostomum. Acellular masses of what was interpreted as cuticle of a molting parasite were found in the lung. A mature female nematode was found encysted in the lung. The identity of that parasite and the cuticle has not been established.

Survival of patients with carcinoma of breast without lymph node metastases in relation to the tumor types.

Carcinoma of breast radical mastectomy specimens were examined. The tumors were classified in accordance with their morphologic appearance. The tumors were also graded on the basis of their cytological makeup and assigned a cytologic malignancy score (CMS). While the classification of tumors was based on the overall pattern of the tumor, the CMS was arrived at by examining the least differentiated portion of the tumor. The following conclusions were suggested by the study: Patients with tumors with high CMS have a poor prognosis, even in the absence of axillary lymph node metastases. It appears reasonable to suggest that patients without overt metastases, but with high CMS, should be considered for treatment with all therapeutic measures available. Such an aggressive approach to patients with low CMS does not appear to be justified.