Multiple eruptive dermatofibromas in a patient with dermatomyositis taking prednisolone and methotrexate.

Dermatofibroma (DF) is a common, benign, dermal tumor, often occurring as a single lesion. Multiple eruptive DFs are rare and usually associated with autoimmune diseases, immunosuppressant therapy, or both. We present the case of a 28-year-old woman with dermatomyositis who developed multiple eruptive DFs after undergoing methotrexate and corticosteroid treatment. Immunosuppressants such as methotrexate and corticosteroids might cause multiple eruptive DFs.

Malignant fibrous histiocytomas induced by 4-(hydroxyamino)quinoline 1-oxide in rats.

Subcutaneous and bone malignant fibrous histiocytomas (MFH) were induced in high incidence in rats by 4-(hydroxyamino)-quinoline 1-oxide (4-HAQO). Subcutaneous MFH were induced locally by repeated weekly injections of 1 mg 4-HAQO/rat for 4 weeks. Between 16 and 48 weeks after the final treatment, 13/15 (87%) male noninbred Wistar rats developed tumors. The histologic subtypes of these tumors were as follows: 11 fibrous, 1 myxoid, and 1 giant cell. Bone MFH were induced between 18 and 25 weeks by implantation of 4-HAQO (8 mg/rat) into the bone marrow of the tibia in 12/14 (86%) male noninbred Fischer 344 rats. The histologic subtypes of these tumors were as follows: 6 fibrous, 4 myxoid, and 2 giant cell. Morphologically, these MFH appeared similar to human MFH.

Tumorigenicity test of 1,3- and 1,8-dinitropyrene in BALB/c mice.

1,3-Dinitropyrene (DNP) and 1,8-DNP (CAS: 42397-65-9) are very potent mutagens and induce a frameshift-type mutation in the Salmonella test system. Each compound was tested for tumorigenicity in BALB/c mice by sc inoculation of 0.05 mg of the compound once a week for 20 weeks. Tumors developed at the site of injection of 1,8-DNP in 6 of 15 mice up to 60 weeks after the first injection. The incidence of tumors was statistically significant at a P-value of less than .05 but not of less than .01. Therefore, the carcinogenicity of 1,8-DNP in BALB/c mice was concluded to be weaker than that of benzo[a]pyrene [(BP) CAS: 50-32-8], which induced a 100% tumor incidence when it was injected at the same dose as that of 1,8-DNP. No tumors occurred at the injection site in mice given 1,3-DNP. Most of the tumors induced by 1,8-DNP and BP showed histologic features characteristic of malignant fibrous histiocytoma.

Carcinogenicity of Camellia sinensis (tea) and some tannin-containing folk medicinal herbs administered subcutaneously in rats.

In an attempt to correlate the high incidence of esophageal carcinoma in natives of certain places with their habit of using herbaceous folk medicines, we performed bioassays of several plant extracts and the fractions prepared from them. Fourteen extracts and fractions from 6 plants were injected sc into NIH Black rats. The tannin fractions from Quercus falcata pagodaefolia, Diospyros virginiana, and Camellia sinensis were very active and produced tumors at the injection site in 66% or more of the treated animals. Tannin fractions from 3 other plants and total aqueous extracts from 5 to 6 tested plants were also tumorigenic rats. The induced tumors were malignant fibrous histiocytomas similar, if not identical, to those encountered in humans. The experiment indicated a possibility of induction of tumor in man by the tested plant materials.

Gross and microscopic pathology of induced prostatic complex tumors arising in Lobund-Wistar rats.

The necessity for additional animal models for prostate cancer has recently been stressed. The Pollard model of chemically induced prostate cancer has received attention in this regard although the histiogenetic origin of these tumors has come under question. We independently studied this model for the development of tumors in the prostate region. The tumors, all of which were adenocarcinomas, first became grossly evident 5 months after induction and ultimately occurred in 71% of the animals. Seventy-three % of the tumors involved only the seminal vesicle, 22% involved other portions of the prostatic complex as well as the seminal vesicle, and 5% were located in the coagulating gland (anterior prostate). Although the majority of tumors arose in or involved the seminal vesicle, this may still be a useful model for the study of human prostate cancer because the tumors are adenocarcinomas, occur in the large majority of animals, are hormonally induced, and have the propensity to metastasize.

Induction of testicular sarcomas in Fischer rats by intratesticular injection of nickel subsulfide.

Nickel subsulfide (Ni3S2) was injected in various amounts into the testis of adult Fischer rats for the study of the acute and chronic effects of Ni3S2 on testicular cells. Rats given injections of 0.6 to 10 mg of Ni3S2 developed an immediate inflammatory response at the site of injection, followed by a delayed, slowly evolving coagulation necrosis of seminiferous tubules and interstitial cells. The extent of testicular necrosis was dose dependent, but at doses of 5 or 10 mg of Ni3S2 the rats invariably developed subtotal destruction of the testis. The testis became atrophic, without regeneration of seminiferous tubules. No damage was seen in the other testis, and no systemic effects were noted. Malignant testicular neoplasms developed in 16 of 19 rats within 20 months after an injection of 10 mg of Ni3S2. These neoplasms were classified by light and electron microscopy as fibrosarcomas, malignant fibrous histiocytomas, and rhabdomyosarcomas. None of the testicular neoplasms was derived from germ cells or genital cord cells. The occurrence of rhabdomyosarcomas in the testis, an organ normally devoid of striated muscle, suggests that Ni3S2 induces malignant transformation of undifferentiated, pluripotential mesenchymal cells.

Skin lesions in patients treated with imatinib mesylate: a 5-year prospective study.

Imatinib mesylate (IM) represents the first-line treatment of patients with chronic myeloid leukemia (CLM) or gastrointestinal stromal tumor (GIST). It presents several side effects. However, less than 10% are nonhematologic including nausea, vomiting, diarrhea, muscle cramps, and cutaneous reactions. The aim of our study was to identify data regarding IM cutaneous adverse effects (AEs) to improve the clinical diagnosis and management of the more frequent side effects. Skin examination should be done before and during IM treatment so that AEs can be diagnosed and treated early with less impact on chemotherapy treatments and on the quality of life of the patient.

Carcinogenicity in rats of the mutagenic compounds 1-nitropyrene and 3-nitrofluoranthene.

1-Nitropyrene and 3-nitrofluoranthene are present in diesel exhaust, in pollutants in air, and were also present in certain xerographic toners and copies. Their carcinogenicities were studied in male F344/DuCrj rats by subcutaneous injection. Sarcomas, mainly malignant fibrous histiocytomas at the site of injection were induced in 8 to 17 (47%) rats by 1-nitropyrene and in 4 of 10 (40%) rats by 3-nitrofluoranthene. Some tumors were serially transplantable in the same strain of rats.

Biomarkers for individual susceptibility to carcinogenic agents: excretion and carcinogenic risk of benzo[a]pyrene metabolites.

In rats exposed to a single intraperitoneal dose of 200 mg/kg of the environmental carcinogen benzo[a]pyrene (BP) in sunflower oil, significant individual variations in excretion of the BP activation (BP-7,8-diol) and deactivation (3-OH-BP) derivatives were found. Most rats developed peritoneal sarcomas. Only the levels of BP-7,8-diol excreted in the urine correlated directly with the latency of tumor formation. After a similar exposure to a dose of 100 mg/kg BP, Macaca fascicularis monkeys excreted smaller quantities than rats of both metabolites. After rats were given 10 intraperitoneal injections each of 10 mg/kg of BP in a water-lipid emulsion, the excreted levels of both metabolites after the first, fifth, and tenth injection were lower than those of the rats that received 200 mg/kg. BP metabolites were also detected in the urine of lung cancer patients who were heavy smokers. The applicability of monitoring the excretion of the BP metabolites to predicting individual cancer risk is discussed.

Carcinogenic effects in the Syrian golden hamster of N-methyl-N-formylhydrazine of the false morel mushroom Gyromitra esculenta.

N-Methyl-N-formylhydrazine (MFH) was administered in drinking water as a 0.0078% solution to randomly bred Syrian golden hamsters for life beginning at 6 weeks of age. The treatment gave rise to benign and malignant liver cell tumors, malignant histiocytomas and tumors of the gall bladder and bile ducts. The tumor incidence in these four treated tissues was 43, 34, 11,8%, while in untreated controls it was 0, 0, 0, 0%, respectively. Histopathologically, tumors were classified as benign hepatomas, liver cell carcinomas, malignant histiocytomas, adenomas and adenocarcinomas of the gall bladder, cholangiomas, and cholangiocarcinomas.

Metamorphosed fibroblasts and their relation to the histogenesis of malignant fibrous histiocytoma in experimental murine model.

Malignant fibrous histiocytoma (MFH) is a clinicopathologically established entity, but its histogenesis remains to be clarified. We have reported the existence of a specific cell type, the "fibrohistiocytoid (FH) cells", in various chronic inflammatory tissues. The FH cells are the metamorphosed fibroblasts and we have revealed the morphological resemblance between FH cells and MFH cells. In the present study we carried out some experiments to ascertain whether the FH cells have a possibility of neoplastic potential for the development of MFH in mice. A total of 50 female Balb/c mice treated with a chemical carcinogen, 9,10 dimethyl-1,2-benzanthracene (DMBA), were examined histopathologically from 8 to 22 weeks after the initial treatment. It was found that 1) the chemically induced tumors in the mice resembled human pleomorphic/ storiform variant of MFH and cells from the tumor were transplantable subcutaneously in the back of another mouse, 2) the tumors were composed mainly of malignant FH cells, and there were many benign FH cells and fibroblasts in granulation tissues obtained at the initial stage of the experiment, 3) all DNA histograms obtained from MFHs were aneuploid and granulation tissues were diploid, and 4) benign FH cells in the granulation tissue appeared to have higher DNA synthesis activity than typical fibroblasts on the basis of bromodeoxyuridine (BrdU) labeling and cytofluorometric studies. From these findings, we suggest that the FH cells are not only a merely morphologically changed fibroblast, but also a biologically ominous cell which may contribute to develop MFH in mice.

In vivo tumouricidal effect of T lymphocytes activated by liposomes containing adriamycin on chemically-induced rat malignant fibrous histiocytoma.

The augmentative effect of liposomes containing adriamycin (LADM) in the host-tumour immune mechanism was assessed using 9,10-dimethyl-1,2-benzanthracene induced rat malignant fibrous histiocytoma (MFH). The antitumour effect of LADM was analyzed using a double grafted tumour system in which F344 rats first received simultaneous s.c. inoculations of MFH cells in both right and left flanks and were then injected with 0.2 mg of LADM into the right tumour on Day 10, 12, and 14. The growth of a remote, non-treated tumour was strongly inhibited, and the infiltration of CD8+ or CD4+ cells at the tumour periphery was histologically revealed. This inhibition was not observed in F344 nu/nu athymic rats. Winn neutralizing assay with T cell-rich splenic lymphocytes from each drug-treated MFH-bearing rat showed that complete regression of the tumour at a low effector/target ratio occurred only in the LADM-treated group. Furthermore, the tumouricidal effects were demonstrated in coexistence with CD8+ cells and CD4+ cells by assay with FACS sorting splenic lymphocytes. These results strongly suggest that intratumoural administration of LADM caused the systemic augmentation of the MFH-bearing host immune mechanism, and that the augmented response after LADM treatment was induced by the cytotoxic CD8+ lymphocytes dependent on the CD4+ lymphocytes.

Induction of malignant fibrous histiocytoma in female Fisher rats by implantation of cyanoacrylate, zirconia, polyvinyl chloride or silicone.

Five kinds of foreign bodies (silicone, cellulose, polyvinyl chloride, zirconia and alkyl-alpha cyanoacrylate) were implanted into subcutaneous tissue of female Fisher rats. Subcutaneous tumors were induced in 27.3, 54.5, 100, 63.6% of rats by silicone rubber, polyvinyl chloride, zirconia and alkyl-alpha-cyanoacrylate, respectively, but not by cellulose. Almost all tumors were composed of a mixture of cells that resembled fibroblasts characterized by the presence of numerous rough-surfaced endoplasmic reticulum and Golgi apparatus, histiocytes characterized by developed endoplasmic reticulum and abundant lysosome, myofibroblasts characterized by the presence of both myofibrils and fibroblast-like structures, and immature mesenchymal cells. In some tumors, the cells exhibited a storiform pattern. Some tumor cells were positively stained by ED2 or anti-muscle actin antibody. The features of induced tumors in rats were consistent with those of human malignant fibrous histiocytoma. A rat malignant fibrous histiocytoma transplanted into the subcutaneous tissue of the syngeneic female Fisher rats grew and metastasized to the lungs.

Metabolism and biological effects of nitropyrene and related compounds.

The aim of this project was to compare the carcinogenicities of 1,3-, 1,6-, and 1,8-dinitropyrene, 1-nitropyrene, and the metabolic phenolic derivatives of 1-nitropyrene. The biochemical goal was to establish how these inert compounds are converted metabolically, by target tissues, to reactive species that can alter the DNA of the susceptible cell. The comparative tumorigenicities were assessed by the use of female CD rats. Control groups consisted of animals that had been given only the solvent, dimethylsulfoxide, which has a low toxicity, to maximize solubility. Equimolar doses (1.7 mumole/ml; 10 mumole/kg body weight) of the compounds were administered to weanling rats by intraperitoneal injection, or by intragastric intubation, three times each week for four weeks, for a total dose of 16 mumoles. Newborn animals were treated by subcutaneous injection of the 1,3-, 1,6-, or 1,8-dinitropyrene or 1-nitropyrene within 24 hours of birth, and at seven weekly intervals, for a total dose of 6.3 mumoles. The possible carcinogenicities of phenolic metabolites of 1-nitropyrene were examined by subcutaneous treatment of newborn animals, and at seven weekly intervals, with 1-nitropyrene, 3-hydroxy-1-nitropyrene, or a mixture of 6-hydroxy-1-nitropyrene and 8-hydroxy-1-nitropyrene (70 mumoles/ml; 100 mumoles/kg body weight; total dose, 63 mumoles). The relative carcinogenicity of 1-nitropyrene in the female Fischer 344 rats was established by the concurrent treatment of appropriate animals. The smaller, inbred Fischer rats received a total dose of 40 mumoles. Subcutaneous and intraperitoneal treatments of weanling female CD rats (70 mumoles/ml; 100 mumoles/kg body weight; 5 weekly injections) with 1-nitropyrene were carried out to explore possible differences because of the different routes of administration in animals of the same age. Dinitropyrenes are much more carcinogenic than 1-nitropyrene (1,6- greater than 1,8- greater than 1,3-dinitropyrene greater than 1-nitropyrene). Phenolic derivatives of 1-nitropyrene are no more carcinogenic than the parent compound. The most likely tumors to be induced in this animal model are malignant fibrous histiocytomas (MFHs), mammary gland tumors, and leukemias. Animals treated with 1,6- or 1,8-dinitropyrene by subcutaneous injection yielded MFHs at the site within 15 weeks of the first injection (i.e., at 15 weeks of age), and this did not permit them to survive more than 20 to 25 weeks. Leukemia developed in these animals within this brief period, but mammary gland tumors were observed only when survival of the animal was not limited by the formation of the more aggressive MFHs.(ABSTRACT TRUNCATED AT 400 WORDS)

[The ultrastructure and histochemical characteristics of the cells of malignant fibrous histiocytoma in rats]. / Ul'trastruktura i gistokhimicheskie osobennosti kletok zlokachestvennoi fibroznoi gistiotsitomy u krys.

Samples of tissue from malignant fibrous histiocytoma of rats induced by subcutaneous injection of paraffin pill-enclosed DMBA were studied for localization of acid phosphatase and non-specific esterases (15 samples) and cell ultrastructure (10). Tumours showed cellular heterogeneity consisting of 5 types of cells: histiocyte-like, fibroblast-like, giant multinuclear xanthomatous and undifferentiated. Acid phosphatase and non-specific esterases were found both in histiocyte-like and fibroblast-like cells which means that those enzymes are not the specific markers of tumors arising from monocytic-macrophagal system. Histochemical and ultrastructural features of experimental malignant fibrous histiocytoma were similar to those of its human analogue.

Differential diagnosis of malignant tumours in the abdominal cavity of rats after intraperitoneal injection of crocidolite or benzo[a]pyrene.

In our investigation (i.p. test), crocidolite and benzo[a]pyrene, both caused a progression from initially reactive, then autonomously transformed proliferation of myofibroblasts and undifferentiated mesenchymal cells to malignant, multidirectionally differentiated (desmin and ED-1 positive) fibro-histiocytic tumours. Immunohistochemically these tumours showed no morphological characteristics (for example co-expression of vimentin and keratin in spindle-shaped tumour cells) of human asbestos-associated malignant mesotheliomas. On the other hand many tumour cells induced by crocidolite and benzo[a]pyrene had an ultrastructural appearance resembling fibroblasts and myofibroblasts. These have been demonstrated in only a few desmoplastic and sarcomatous mesotheliomas in human beings. None of the tumours revealed the typical ultrastructural features of epitheloid or transitional mesotheliomas. Apparently, both carcinogenic substances induce the transformation of undifferentiated pluripotent mesenchymal cells in rat peritoneum, regardless of their localization in the submesothelial compartment or perivascular connective tissue (preferentially after crocidolite application) or in the connective tissue pseudocapsule of major benzo[a]pyrene containing beeswax/tricaprylin depots in the mesometrium and mesenterial fatty tissue. In this way asbestos fibres in this animal experiment do not seem to induce an arrest in differentiation of intermediate or immature mesothelial cells as supposed formerly, but rather affect undifferentiated mesenchyme cells and myofibroblasts. This is an explanation for the immunohistochemical expression of markers of muscular differentiation in these tumour cells, which is known to occur in human malignant fibro-histiocytic tumours. If supplementary immunohistochemical investigations with different keratin antibodies also fail to confirm the mesothelial differentiation of the tumours induced in our i.p. test, the decision to call them "mesotheliomas" should be reconsidered. Further immuno-transmission-electron microscopical investigations with intermediate filament or macrophage antibodies are needed to clarify whether the term malignant "fibrohistiocytic sarcoma", "mesenchymoma" or "mesothelioblastoma" would be more correct from the morphological point of view.

Lack of an antitumoral effect of immunomodulatory galactoside-specific mistletoe lectin on N-methyl-N-nitrosourea-induced urinary bladder carcinogenesis in rats.

The aim of the present animal experiment was to study the effect of galactoside-specific lectin or agglutinin (VAA) from mistletoe (Viscum album L.) on chemically induced tumor development in the urinary bladder of rats. Since VAA has been shown to exert a remarkable immunomodulating effect, any change in tumor formation would indicate a lectin-triggered immune control of urothelial carcinogenesis in the used model. To produce vesical neoplasms the direct-acting urothelial carcinogen N-methyl-N-nitrosourea (MNU) was administered at a single intravesical dose (7.5 mg/kg body weight). Highly purified VAA was given subcutaneously twice a week at the immunomodulatory dose of 1 ng/kg body weight over a period of 6 months during the critical phases of tumor development. After a total experimental time of 15 months the incidence of epithelial bladder tumors was 29.3% in controls versus 27.9% in rats additionally receiving the lectin and thus not significantly different in both experimental groups. There were, moreover, no substantial differences in the histopathologic spectrum of epithelial tumors induced, their patterns of growth, grades of cellular malignancy and local extension. The frequency and histopathology of mesenchymal bladder tumors as well as the incidence and morphology of carcinomas of the ureters and renal pelves also proved to be similar in controls and in rats treated with VAA. In conclusion, the present data provide no evidence for a modifying or even inhibitory effect of the immunomodulatory galactoside-specific mistletoe lectin on experimental urothelial carcinogenesis.