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Fibrosarcoma of the urinary bladder. Study of a case showing extensive chondroid differentiation.

A case of primary fibrosarcoma of the urinary bladder showing extensive chondroid differentiation was studied by light microscopy and immunofluorescent microscopy using tissue-specific antibodies against intermediate filaments. The tumor cells were uniformly and positively labeled with vimentin antibodies and were negative for desmin and keratin, thus confirming the nonmuscle mesenchymal origin of the neoplasm. The value of intermediate filament typing in the differential diagnosis of spindle cell tumors of the urinary bladder is discussed, and a review of the literature on the subject is presented. It is postulated that the retained capacity for continued differentiation displayed by this tumor may account for the relatively better prognosis observed for this patient.

Aged↗

Radiosensitivity of late recurrences following radiotherapy of murine fibrosarcomas.

Radiosensitivity of late recurrent tumors which emerged after radiotherapy was investigated. Tumors observed were fibrosarcomas. Recurrences emerged in the irradiated area approximately 200 days after a 50% tumor control dose of radiation of 60Co gamma rays or mixed irradiation with fast neutrons and gamma rays. The recurrent and radiation-induced tumors were differentiated by karyotype analysis. Once transplanted into fresh mice, the recurrent tumors grew more slowly than the original tumor. Tumorigenicity of the late recurrences was lower than that of the original tumor. Radiosensitivity of the late recurrences, which was examined using methods to assess control, tumor growth delay, and colony forming assays, was significantly higher than that of the original tumor. D0 values of hypoxic tumor cells were significantly smaller in two of the three recurrences compared to the original tumor. Oxic cells, when irradiated in vitro, also showed smaller D0 values for the recurrent tumors than the original tumor. Hypoxic cell fractions were between 0 and 14% in the late recurrences and 10% in the original tumor. These results are consistent with the hypothesis that radiotherapy causes mutation of tumor cells which results in increased radiosensitivity of surviving tumor cells.

Animals↗

[Effect of combined use of radiation and twice intratumor administration of OK-432 at one week intervals against a murine fibrosarcoma (NFSA)].

Effect of combination use of radiation and multiple administration of OK-432 was studied using a radio-resistant and weakly immunogenic murine fibrosarcoma (NFSa) originated spontaneously in a C3H female mouse. Mice implanted the tumor in the leg were locally irradiated with 40 Gy of gamma rays and locally administered total 8 KE of OK-432. The first group was given 1 KE daily for 8 days, 2 KE every other day in the 2nd group, 4 KE at 1 week interval in the 3rd group and 8 KE immediately after irradiation in the 4th group. The tumor volume at day 19 after irradiation was compared. The tumor growth inhibitory effect was observed in the 3rd group (p less than 0.01) and 4th group (p less than 0.05) compared to the group given radiation alone. This effect was seen at even more smaller dose of OK-432 as 0.5 KE by 2 times administration at 1 week interval. The effect of route of OK-432 administration was studied comparing the tumor volume at day 22. OK-432 was given 2 times at 1 week interval. A significant difference was seen in the group given OK-432 locally compared to the control group given radiation alone (p less than 0.001). There were no significant differences between the groups given OK-432 by the routes of i.p., s.c. i.v. and the control group. TCD50 value was examined giving OK-432 4 KE on the day and 2 KE on day 7 after irradiation. TCD50 value in the group treated with irradiation alone was 83.5 (79.6-87.4) Gy and the group given combination therapy with OK-432 was 60.7 (55.9-65.4) Gy. Two times OK-432 administration at 1 week interval appears to potentiate the radiation response by about 23 Gy.

Animals↗

Polycythemia associated with renal fibrosarcoma in a dog.

A 10-year-old Beagle-type dog with intermittent vomiting and anorexia had an absolute polycythemic condition. A renal mass was detected and removed by total nephrectomy. After surgery, the hematologic values returned to normal, suggesting that the tumor was the cause of the polycythemia. The histologic diagnosis was fibrosarcoma. In dogs, secondary polycythemia has otherwise been reported with renal carcinoma and lymphosarcoma.

Animals↗

Sequencing of trimodality therapy [cis-diamminedichloroplatinum(II)/hyperthermia/radiation] as determined by tumor growth delay and tumor cell survival in the FSaIIC fibrosarcoma.

In order to improve local control of tumors over that achievable with local hyperthermia and radiation, we are testing the use of systemic cis-diamminedichloroplatinum(II) (CDDP) in conjunction with the other two modalities. In the FSaIIC fibrosarcoma, growth delay experiments indicated that the use of any two modalities resulted in at least additive effects on growth delay. When the trimodality treatment was tested, the sequence CDDP followed by hyperthermia followed by X-ray produced a growth delay of approximately 25 days which was superior to the growth delay produced by the sequences CDDP, X-ray, and hyperthermia (19 days) and X-ray, CDDP and hyperthermia (14 days). In excision experiments, also performed in the FSaIIC tumor system, we again observed clearly superior cytotoxicity in the sequence CDDP, hyperthermia, and X-rays over the other sequences tested. Our results indicate that scheduling CDDP just prior to heating and following the heat treatment with the radiation fractions results in the best tumor cell kill, probably because this sequence takes maximum advantage of the radiosensitizing properties of the combined heat-CDDP treatment. In addition, the strong cytotoxic interaction between CDDP and hyperthermia is also optimized by this scheduling. We believe these results have significant clinical implications.

Animals↗

Glucocorticoid receptor-mediated effects on rat fibrosarcoma growth.

Glucocorticoid receptors are present in most normal and malignant mammalian cells. To examine the hypothesis that the growth of methylcholanthrene-induced malignant sarcoma is glucocorticoid dependent, we evaluated the behavior of malignant fibrosarcoma (MCA) in adrenalectomized rats treated with either normal saline or deoxycorticosterone acetate and in intact rats treated with placebo or with the glucocorticoid receptor antagonist RU 486. Survival, tumor weight, and loss of body weight (an index of cachexia) were measured. In MCA-bearing rats, neither survival nor loss of body weight was affected by bilateral adrenalectomy or by treatment with RU 486. Tumor weight and time-integrated tumor volume, however, were significantly less in bilaterally adrenalectomized rats without deoxycorticosterone acetate replacement than in animals treated with deoxycorticosterone acetate. Similarly, tumor weight and time-integrated tumor volume were less in intact animals treated with RU 486 than in intact animals treated with placebo. The glucocorticoid receptors in the tumor cells had similar binding capacity (Ro) and equilibrium dissociation constant (Kd) as in control rat fibroblasts. These results suggest that the growth of MCA sarcoma cells is partially dependent upon glucocorticoids. This effect of glucocorticoids, however, was not of sufficient magnitude to improve survival and prevent cachexia. We conclude that glucocorticoids appear to influence MCA sarcoma growth in the rat, and that glucocorticoid receptor blockade, perhaps in combination with other antitumor agents, merits future study in the treatment of malignant tumors.

Adrenalectomy↗

Single and fractionated whole body hyperthermia in murine fibrosarcoma.

The effects of single and multiple fractionated whole body hyperthermia (WBH) 41.5 degrees C on benzo(a) pyrene induced fibrosarcoma of mice were evaluated in terms of tumour response and systemic alterations of the host. While single exposure of WBH(S) 2 hrs, caused moderate inhibition of tumours and increase in the median survival time, multiple fractionated exposures [WBH(M)] caused significant enhancement of tumours with decrease in mean survival time. Tumoricidal effects associated with increased acid phosphatase and beta-glucuronidase activity were observed in both the regimes of WBH. In WBH(M) the development of thermotolerance was indicated by decreased activity of these enzymes in subsequent treatments. Elevation of plasma corticosterone and significant lymphocytopenia occurred in both the regimes. The alterations were transient in WBH(S) but persisted for more than two weeks in WBH(M), indicating that tumour enhancement is possibly influenced by corticosterone-mediated immunosuppression. In the WBH(M), the tumoricidal effects were counteracted and surpassed by the growth stimulatory physiological alterations of the host. Therefore the mode of application of WBH and the systemic responses of the host are critical factors that should be considered in designing therapeutic regimes with WBH.

Acid Phosphatase↗

Response of radiation-induced fibrosarcoma-1 in mice to cyclophosphamide monitored by in vivo 31P nuclear magnetic resonance spectroscopy.

In vivo 31P nuclear magnetic resonance spectroscopy has been used to examine the RIF-1 fibrosarcoma in mice during untreated growth and following chemotherapy with cyclophosphamide. Levels of inorganic phosphate increase relative to phosphocreatine or nucleoside triphosphates during early untreated growth. After the tumor reaches a volume of approximately 1 g, no further decrease in energy level is observed. Following treatment with cyclophosphamide, tumor phosphorus metabolite ratios and pH are significantly altered, compared to untreated age-matched controls. During the growth delay period following chemotherapy there is a significant reduction in the ratio of inorganic phosphate to other phosphate metabolites, compared to age-matched controls. In addition, a more alkaline pH is observed in the tumors of treated animals. When the growth delay period ends, nuclear magnetic resonance spectra return to pretreatment patterns. The magnitude of the differences in 31P nuclear magnetic resonance spectral parameters between treated animals and untreated controls is dose dependent. However, doses of cyclophosphamide above 200 mg/kg do not result in earlier spectroscopic alterations, nor in larger effects by Day 3 after treatment, even though clonogenic cell killing and growth delay are greater at these higher doses.

Animals↗

Marked granulocytosis in C57BL/6 mice bearing a transplanted BMT-11 fibrosarcoma.

When a 3-methylcholanthrene (CAS: 56-49-5)-induced fibrosarcoma, BMT-11, and its eight clones were transplanted sc into syngeneic C57BL/6 mice, leukemoid reaction characterized by a progressive increase in peripheral white blood cells (WBCs) and by splenomegaly was observed as the tumors grew. The WBC count reached about forty-fold of the normal level, and more than 90% of WBCs were found to be polymorphonuclear leukocytes. The increase in WBCs was correlated with tumor size, and its count decreased to normal level within 7 days after surgical excision of subcutaneous tumors. Moreover, a high level of colony-stimulating activity was detected in the supernatant of BMT-11 culture. These results suggest that the colony-stimulating factor produced by BMT-11 cells caused granulocytosis in mice. This is the first report of the marked degree of granulocytosis induced by a transplanted tumor in C57BL/6 strain mice.

Animals↗

Toxicity, radiation sensitivity modification, and combined drug effects of ascorbic acid with misonidazole in vivo on FSaII murine fibrosarcomas.

Ascorbic acid (ASC) has been shown to radioprotect nonmalignant tissue and to enhance the effects of misonidazole (MISO) on hypoxic cells in vitro. Since ASC is minimally toxic, it is an interesting candidate for improving the radiotherapeutic gain factor in vivo. The in vivo radiomodifying effects of ASC on a C3H/fSed murine fibrosarcoma (FSaII), on normal skin, and on bone marrow were determined with the use of the tumor growth delay and TCD50 (i.e., radiation dose required to control 50% of treated tumors for a minimum of 120 days) assays and the RD50 (i.e., dose required to cause a peak skin reaction of 2 in 50% of treated hind limbs) and LD50 (i.e., whole-body radiation lethal dose) assays, respectively. ASC was buffered to pH 7.35 and delivered ip at a dose of 4.5 mg g-1 body weight. ASC did not modify tumor growth delay induced by radiation or the TCD50 [87.1 Gy (control) vs. 85.6 Gy (ASC)]. Normal tissues, however, were radioprotected by ASC. RD50 values for 2+ acute skin reactions were 46.4 and 55.7 Gy for control and ASC-treated subjects, respectively; LD50 (30 days) values were 7.2 and 8.5 Gy. The enhancement ratios for skin and bone marrow were 1.20 and 1.18, and 95% confidence limits were (1.07 ... 1.34) and (1.14 ... 1.23), respectively. The therapeutic gain factor was 1.22 calculated as the ratio of the TCD50 and the reference normal tissue (RD50 or LD50). When ASC and MISO were combined, ASC reduced the in vivo radiosensitizing effects of MISO.

Animals↗

Enhancement of therapeutic effects of recombinant interleukin 2 on a transplantable rat fibrosarcoma by the use of a sustained release vehicle, pluronic gel.

We have tested the feasibility of pluronic F-127 gel (PLF-127; a polyoxyethylene-polyoxypropylene surface active block copolymer) as a sustained release vehicle for topical administration of interleukin 2 (IL-2) in order to enhance the therapeutic effects of IL-2 against a rat fibrosarcoma, KMT-17. Injection of human DNA recombinant IL-2 (3 X 10(4) units s.c.) in 30% (w/w) PLF-127 into rats provided detectable serum IL-2 levels for up to 10 h, while injection of IL-2 alone provided detectable IL-2 levels for 3 h. When, following s.c. inoculation with 1 X 10(5) KMT-17 tumor cells into rats, IL-2 (6 X 10(4) units/day) in PLF-127 gels was injected s.c. around the growing tumor inoculum every 2 days for 10 days from Day 1 to Day 19, the survival days of rats were more prolonged [mean survival day, 32.3 +/- 5.4 (SD)] as compared with that of rats treated with saline [20.7 +/- 2.1] than mean survival days of rats treated with IL-2 alone [27.3 +/- 4.5] or PLF-127 alone [22.9 +/- 3.3]. Moreover, the span of mean survival days of rats treated with IL-2 in PLF-127 locally (31.7 +/- 5.9) was much longer than that of rats given IL-2 in PLF-127 systemically (22.8 +/- 3.4). By means of a Winn assay, stronger tumor neutralizing activities were observed in regional lymph node cells obtained from tumor bearing rats treated with IL-2 in PLF-127 than were observed in lymph node cells from rats treated with IL-2 alone or PLF-127 alone (percentage of inhibition, 90.3, 12.2, and -15.5%, respectively). The therapeutic effects of IL-2 were thus found to be consistent with the antitumor activity in regional lymph node cells. These results suggest that the enhanced therapeutic effects of IL-2 in PLF-127 are due to enhancement of antitumor immune responses induced by sustained IL-2 activity at the tumor sites.

Animals↗

T-lymphocytes and macrophages in primary murine fibrosarcomas at different stages in their progression.

The relative contribution of lymphocytes, macrophages, and granulocytes to the cell content of primary 3-methyl-cholanthrene-induced murine fibrosarcomas was determined at different stages in their progression by differential cell analysis on enzyme-derived single-cell suspensions. Furthermore, immunohistological analyses were performed on the tumors to detect, quantitate, and determine the distribution of T-lymphocytes and macrophages. The T-lymphocyte content of small tumors was very high, and the T-cells were distributed throughout the tumor mass. As the tumor increased in size, there was a marked decrease in the relative T-cell content; most were located at the tumor periphery. Macrophages were present in significant numers in all tumors and appeared to increase in number as the tumors increased in size. Macrophages were distributed throughout the tumor mass, but generally they were more densely distributed near the tumor periphery. Granulocytes were present in low numbers in all tumors. Yeast phagocytosis was used to assess the functional capacity of the macrophage population. The phagocytic capacity of the macrophages was low in the small tumors, increased significantly as the tumors progressed, but dropped to relatively low levels in large tumors. The results represent a preliminary attempt to characterize the dynamics of host cell infiltration of primary immunogenic tumors.

Animals↗

Monoclonal antibodies to human 54,000 molecular weight plasminogen activator inhibitor from fibrosarcoma cells--inhibitor neutralization and one-step affinity purification.

Mouse monoclonal antibodies were derived against a plasminogen activator inhibitor with a mol. wt. of approximately 54,000 (54 K) from the human fibrosarcoma cell line HT-1080. Screening for hybrids producing antibodies directed against the inhibitor was performed with enzyme-linked immunosorbent assay and SDS-polyacrylamide gel electrophoresis (SDS-PAGE) followed by immunoblotting. Four clones of hybridomas producing IgG1 antibodies were further characterized. The inhibitor was purified approximately 50-fold to homogeneity from conditioned cell culture fluid with a yield of approximately 85% by a one-step procedure using Sepharose-conjugated monoclonal antibody. In the 125I-fibrin plate assay one of the antibodies neutralized the effect of the inhibitor on urokinase-type plasminogen activator. Two of the antibodies bound complexes between urokinase-type plasminogen activator and inhibitor while the remaining two antibodies did not. The antibodies could be used for immunocytochemical localization of the inhibitor in HT-1080 cells. All four antibodies cross-reacted with a plasminogen activator inhibitor derived from cultured human umbilical cord endothelial cells.

Animals↗

Association in the expression of Kirsten-ras oncogene and the major histocompatibility complex class I antigens in fibrosarcoma tumor cell variants exhibiting different metastatic capabilities.

The metastatic properties of the methylcholanthrene-induced T-10 sarcoma tumor variants which originated in C3H x C57Bl/6 F1 mice are correlated with the relative expression of class I major histocompatibility complex antigens. Both the nonmetastatic and the highly metastatic clones were found to lack the H-2K region-controlled H-2Kb and H-2Kk antigens. However, the nonmetastatic clones express only the H-2Db molecule whereas the metastatic clones express both the H-2Db and the H-2Dk molecules. Transfection of the highly metastatic lines with cloned H-2K genes (Kb, Kk) reduced their tumorigenicity and abolished the formation of metastasis in syngeneic mice, while the transfection of the nonmetastatic lines with cloned H-2Dk genes resulted in shifting the cells to the metastatic phenotype. The present study is aimed to investigate the expression of protooncogenes in the T-10 fibrosarcoma lines that exhibit distinct metastatic properties in correlation with the expressed H-2 antigens. The major oncogene which showed differential expression in the T-10 clones is Ki-ras. The amounts of specific Ki-ras messenger RNA and the Ki-ras Mr 21,000 protein are expressed in elevated levels in the H-2Dk-negative nonmetastatic clones in comparison with a low level of expression in the H-2Dk-positive highly metastatic clones. Expression of H-2K antigens following transfection with cloned H-2K genes had no effect on the expressed Ki-ras oncogene in the T-10 clones. However, transfection of the nonmetastatic cells with the cloned H-2Dk gene resulted in shifting of the cells to a highly metastatic phenotype and in reduction of the expressed c-Ki-ras oncogene.

Animals↗

Immunogenic variants of a murine fibrosarcoma induced by mutagenesis: requirement of viable cells for antigen-specific cross-protection.

The purpose of the study was to investigate the immunological and biological consequences of neoantigen expression by immunogenic tumor variants (Imm+) following in vitro treatment with the mutagen 1-methyl-3-nitro-1-nitrosoguanidine. The weakly immunogenic murine fibrosarcoma MCA-F was used because we have previously characterized the tumor-specific transplantation antigen expressed by this tumor. Immunogenic variant clones were obtained at high frequency following four treatments with 1-methyl-3-nitro-1-nitrosoguanidine. The immunogenicity of the Imm+ clones was confirmed by their progressive growth in immunosuppressed C3H/HeN mice and their lack of growth in normal syngeneic (C3H/HeN mice. The immune response engendered in immunocompetent mice after a single immunization with viable Imm+ cells was tumor specific, completely protecting hosts against challenge with 10,000-fold the minimum tumorigenic dose of parental MCA-F cells, but not against 10 minimum tumorigenic doses of the non-cross-reactive tumor MCA-D. The strong cross-protection elicited by Imm+ neoantigens against the parental tumor-specific transplantation antigen was not observed when soluble extracts or isolated plasma membranes of Imm+ cells were used for immunization. Immunogenic variant cells inactivated using either mitomycin C or gamma-irradiation also demonstrated a significantly diminished immunoprotective activity against challenge with the parent tumor. However, inactivated Imm+ cells and their isolated plasma membranes still expressed sufficient neoantigen to completely protect mice against homotypic Imm+, but not parental challenge. These results suggest that (a) the MCA-F Imm+ variants express neoantigens capable of engendering a strong specific as well as cross-protective immunity against challenge with either the parent or the variant and (b) the associative recognition of neoantigen and TSTA that results in strong cross-protection against challenge with the parent tumor requires immunization with viable Imm+ cells for full expression of the immunogenic phenotype.

Animals↗

Omental fibrosarcoma in a horse.

A 13-year-old Thoroughbred mare had a 2-week history of weight loss and intermittent fever. Examination of abdominal and pleural fluid revealed peritonitis and pleuritis. Ultrasonography of the ventral abdominal midline revealed an intra-abdominal mass. Exploratory celiotomy was performed, but the mass was not surgically excisable. The mare was euthanatized and necropsied. Histologically, the mass was determined to be a fibrosarcoma of omental origin.

Animals↗

Nasomaxillary fibrosarcomas in three young horses.

Nasomaxillary fibrosarcoma was diagnosed in 3 young horses. Clinical signs included epiphora, facial swelling, dyspnea, unilateral serosanguineous nasal discharge, or an external mass. Physical examination, radiography, and cytology were important diagnostic adjuncts. The definitive diagnosis in each case was based on biopsy. In one case, surgical removal of the tumor and extensive curettage of the affected sinus resulted in extended remission from neoplastic disease.

Animals↗

[A case of fibrosarcoma of the kidney extending into the inferior vena cava].

A case of fibrosarcoma of the kidney extending into the inferior vena cava with intraoperative development of massive neoplastic pulmonary emboli is reported. A 38-year-old man was admitted to our hospital because of right renal tumor with gross hematuria, right flank pain and abdominal tumor. Inferior venacavograms and computerized tomography demonstrated almost total occlusion of the abdominal part of the vena cava by tumor thrombi. No signs of inferior vena caval involvement were present. Intraoperative pulmonary neoplastic emboli suddenly occurred after right nephrectomy was performed. Immediately, pulmonary thrombectomy was performed with extra-corporeal circulation. Postoperatively, pulse, blood pressure and ventilation were stable, but the patient remained unconscious and neurologic signs gradually deteriorated. Computerized tomography of the brain showed diffuse brain edema and infarctions. The patient died of cardiopulmonary insufficiency with multiple pulmonary metastasis 8 months postoperatively. We emphasize the risk of fragmentation and migration of the tumor thrombi during surgical treatment of neoplasm of the kidney invading the inferior vena cava.

Adult↗