Effect of polyamine oxidase inhibition on the colonic malignant transformation process induced by 1,2-dimethylhydrazine.

Recent studies of colon adenocarcinomas in humans and experimentally induced colonic tumors in rodents have demonstrated selective elevations in the level of N1-acetylspermidine in these malignant tissues. The exact relationship of these alterations in acetylated polyamine levels to the malignant transformation process, however, remains unclear. In order to clarify this issue, rats were given s.c. injections of 1,2-dimethylhydrazine (DMH; 20 mg/kg body wt/week) or diluent for up to 26 weeks. After 10 weeks of carcinogen treatment, one-half of the animals in each group were also concomitantly given i.p. injections of MDL 72527 (20 mg/kg body wt/week), a specific inhibitor of polyamine oxidase, until they were killed. Animals were killed after 15 weeks of DMH treatment and polyamine levels as well as the activities of polyamine oxidase, ornithine decarboxylase and spermidine-N1-acetyltransferase were measured and compared in rat proximal and distal colonic mucosa of each group. Polyamine levels were also assessed in each of these groups after 26 weeks of treatment with this carcinogen +/- MDL 72527. In addition, in view of recent studies that have indicated that polyamines may influence certain oncogenes in human colonic carcinoma cells, tumors from DMH +/- MDL 72527 were analyzed for K-ras mutations. The results of these experiments demonstrated for the first time that: (i) MDL 72527 was a specific inhibitor of polyamine oxidase in normal and malignant colonic tissue; (ii) concomitant administration of this agent with DMH enhanced the elevation of colonic N1-acetylspermidine and significantly reduced the mean colonic tumor burden, as assessed by total tumor area per rat, produced by this carcinogen alone; (iii) analysis of K-ras mutations revealed a similar incidence (62-69%) in adenocarcinomas for both groups (+/- MDL 72527); (iv) however, analysis of the K-ras-mutated and non-mutated tumors revealed that in both carcinogen-treated groups (+/- MDL 72527), tumors with such mutations were smaller than their counterparts without such genetic alterations. Moreover, MDL 72527 reduced the average size of tumors, with and without such mutations, to a similar extent.

Histiocytic appearance of metastatic lobular breast carcinoma.

Autopsy findings in a case of widely disseminated lobular breast carcinoma showed an unusual histiocytoid appearance in metastases to the uterus and parathyroid gland. This morphology for breast carcinoma has been previously reported in eyelid metastases. Recognition of this pattern in other metastatic sites has important diagnostic and therapeutic implications. Problems might have arisen if the polypoid uterine mass had been the presenting lesion during life. We also review the occurrence of metastatic breast carcinoma in the uterus and parathyroid gland.

IgA deposition in liver in alcoholic liver disease. An index of progressive injury.

A retrospective study was done to evaluate the prognostic importance of the patterns of IgA deposition in the liver in alcoholic liver disease. The patterns of IgA deposition in the liver were determined by direct immunofluorescence with fluorescein conjugated rabbit antihuman IgA. Twenty of 40 patients showed a characteristic continuous pattern, and 20 patients showed the nonspecific discontinuous pattern of IgA deposition in the liver. Alcoholic liver disease progressed considerably in 14 (70%) of the 20 patients with an initial continuous pattern and in three (15%) of the 20 patients with an initial discontinuous pattern. Alcoholic liver disease did not progress in six (30%) of 20 patients with an initial continuous pattern and in 17 (85%) of the 20 patients with an initial discontinuous pattern of IgA deposition in the liver.

IgA subclasses in liver tissues in alcoholic liver disease.

Examination of liver biopsy specimens from 59 patients with alcoholic liver disease and 21 nonalcoholics by immunofluorescence and immunoperoxidase methods using fluorescein-conjugated and peroxidase-labeled antisera against IgA, IgA1, IgA2, and S-IgA showed that 47 of 59 biopsy specimens from alcoholics and 0 of 21 from non-alcoholics showed a "continuous" pattern of IgA and IgA-subclass deposition (P less than 0.001). Grading the intensity of immunofluorescence on 1-4 scale, biopsies with the continuous pattern showed grade 3-4 activity against IgA2 and S-IgA and only grade 1-2 activity against IgA1. Biopsies with the discontinuous pattern showed only grade 1-2 activity against S-IgA, IgA2, and IgA1. Grade 3-4 activity was persistent in all the 47 specimens with the continuous pattern, despite pretreatment with blocking anti-IgA1, whereas 20 and 38 biopsies showed the same activity after blocking with anti-IgA2 and anti-S-IgA sera, respectively. It is concluded from these studies that IgA2 subclass formed a major subclass component contributing to the continuous pattern of IgA deposition in hepatic tissues and that the major source for this IgA in alcoholics was probably derived from the gastrointestinal tract.

IgA deposits in skin in alcoholic liver disease.

IgA deposition in the liver in a characteristic continuous pattern is a consistent finding confirming the diagnosis of alcoholic liver disease. This study demonstrates a correlation between characteristic IgA deposition in the liver and IgA deposition in and around superficial dermal capillaries in alcoholic liver disease. Simultaneous liver and skin biopsies from nineteen patients with established alcoholic liver disease and eight patients with nonalcohol-related diseases of the liver were studied using standard immunofluorescent and immunoperoxidase methods. Fourteen of the nineteen alcoholic patients showed the characteristic pattern of IgA deposition in the liver, twelve of these fourteen patients showed IgA deposits in and around superficial dermal capillaries, and of these twelve patients, nine showed concurrent deposits of C3 in the skin capillaries. None of the eight nonalcoholic control patients showed either characteristic liver IgA deposits or any dermal deposits. Biopsy of clinically normal skin can be of adjunctive aid in the confirmation of alcoholic liver disease.

The effects of embolectomy-thrombectomy catheters on vascular architecture.

The purpose of this report is to describe the evolution of an embolectomy-thrombectomy catheter (ETC) injury over a six week period. Carotid arteries and jugular veins in six adult dogs were subjected to ETC withdrawals at a standard velocity and balloon size. Vascular segments were excised as early as one hour and as late as six weeks. The specimens were prepared for light, scanning electron and transmission electron microscopic examination. In early specimens, arteries and veins showed endothelial denudation followed by regeneration. In later specimens, the arteries showed progressive disruption of the internal elastic lamina and marked subendothelial proliferation (arteriosclerosis). By the sixth week the artery's intima was equal in thickness to the media. The veins showed only regenerating endothelium without alterations of the subendothelium. Exposure of canine vasculature to ETC procedures caused pronounced transmural damage in the arteries and only endothelial alterations in the veins.

Patterns of IgA deposition in liver tissues in alcoholic liver disease.

Observations in 136 liver biopsies from patients with alcoholic and nonalcoholic liver diseases reveal that IgA deposition in liver tissues appears to have a high degree of morphologic specificity for alcohol injury. Using a direct immunofluorescence technic with fluorescein-conjugated anti-IgG, anti-IgA, anti-IgM, and anti-C1q, four different staining patterns are recognized. These are labelled as "continuous," "discontinuous," "granular," and "pericellular" types depending on their morphologic characteristics and distribution patterns. Fifty of 64 biopsies from alcoholics showed a "continuous" pattern of anti-IgA activity while only three of 72 biopsies from nonalcoholics showed a similar pattern (P less than 0.001). A "pericellular" pattern of anti-IgA activity appears to indicate a more aggressive behavior of alcoholic liver disease. "Continuous" and "pericellular" patterns are seen in "chronic active hepatitis of alcoholics" but not in chronic active hepatitis in nonalcoholics. Anti-IgM activity appears to indicate chronicity of the disease process but does not have any specificity.

Postirradiation malignant fibrous histiocytoma of the lung. Demonstration of alpha 1-antitrypsin-like material in neoplastic cells.

A metastasizing fibrous histiocytoma arising in the lung of a patient who received radiation therapy and long-term chemotherapy for malignant lymphoma is presented. Ultrastructural studies revealed fibroblast-like and histiocyte-like cells, cells of intermediate type showing ultrastructural features of both fibroblast-like and histiocyte-like cells, primitive mesenchymal cells, multinucleate tumor cells, and xanthomatous cells. The neoplastic cells showed dilated rough endoplasmic reticula with intracisternal accumulation of electron-dense material forming lattice-like structures. Direct immunofluorescence staining of the neoplastic cells using antihuman alpha 1-antitrypsin showed specific activity, with fluorescent deposits exhibiting interlacing globular formations. These findings and their implications are discussed.

Ultrastructural aspects of mucinous (colloid) breast carcinoma.

Seven cases of mucinous (colloid) breast carcinoma were studied by electron microscopy. In addition to the predictably abundant mucosubstance production, the following observations merit elaboration: 1) absence of myoepithelial differentiation and basal lamina deposition, 2) notably developed cytoplasmic filamentous systems and relatively scarce lysosomes, 3) frequent and apparently well-developed intercellular junctions, and 4) a distinct paucity of vessels in the tumors' stroma. The rather favorable clinical prognosis of mucinous breast carcinoma despite the absence of myoepithelial differentiation and basal lamina deposition parallel observations made on medullary and tubular breast carcinomas, thus confirming that those parameters, however important, are not the sole determinants of an aggresive behavior. The conspicuous cytoplasmic filaments appear to be neither true myoepithelial filaments or tonfilaments. The peculiar arrangement of these contractile proteins and the suspected sarcity of lysosomal collagenases may be reflected in the rather low invasiveness of these carcinomas. Another factor that may impact favorably on the cohesiveness of these neoplastic cell clusters is the presence of abundant and well-developed intercellular junctions. We further speculate that the paucity of stromal vessels in these neoplasms may be the result of as yet unidentified factors that might inhibit angiogenesis.