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Angiosarcoma of serous membranes.

Three angiosarcomas of serous membrane are described. One originated in peritoneum, one in pleura, and one in pericardium. The tumor arising in peritoneum was a cystic lymphangiosarcoma and may have been caused by previous therapeutic irradiation for carcinoma of the endometrium. This tumor invaded the peritoneal and right pleural cavities extensively and thus resembled diffuse mesothelioma in its behavior. The tumors arising in pleura and pericardium were hemangiosarcomas.

Aged↗

Malignant neoplasia of canine ribs: clinical, radiographic, and pathologic findings.

An analysis was made of 17 cases of microscopically proven rib neoplasms, with the objective of evaluating the variability of clinical and radiographic findings, the neoplastic cell types, the occurrence of metastases, and the survival time following the diagnosis. In 15 dogs with primary rib neoplasms and in 2 dogs with secondary (presumably metastatic) rib neoplasms, the clinical signs commonly included dyspnea and a localized swelling on the thoracic wall. For the dogs with primary rib neoplasms, the mean age was 4.5 years, with a range of 1.3 to 16 years. On radiography, rib osteolysis, extra and/or intrathoracic soft tissue masses often containing areas of mineralization, and pleural effusion were commonly identified. Ribs 5 through 9 were the most commonly affected and the right side was involved twice as often as the left side. Osteosarcoma was the most frequently diagnosed tumor, but chondrosarcomas and hemangiosarcoma were also found. At necropsy, over 50% of the dogs with primary rib neoplasms had metastases in the lungs. Less than 10% of the dogs with primary rib osteosarcomas survived more than 4 months after the diagnosis.

Animals↗

Paraneoplastic bullous stomatitis in a horse.

An adult horse with a 2-month history of anorexia, ataxia, and oral blisters had developed these clinical signs just prior to the appearance and growth of a cervical mass. Bullous stomatitis was characterized histologically as subepidermal clefting. Clinical signs were unresponsive to treatment with antibiotics or corticosteroids; however, surgical removal of the mass coincided with remission of all signs. Histologic findings of the mass were consistent with hemangiosarcoma. Results of indirect immunofluorescence and immunoprecipitation on frozen serum from the horse were characteristic of paraneoplastic pemphigus in human beings, a newly recognized mucocutaneous autoimmune disease associated with neoplasia.

Animals↗

Chylous ascites in cats: nine cases (1978-1993).

Medical records of 9 cats with chylous ascites that underwent exploratory celiotomy were reviewed. In 7 cats, chylous ascites was associated with intra-abdominal neoplasia: 4 cats had an unresectable tumor (hemangiosarcoma, 3 cats; paraganglioma, 1 cat) within the mesenteric root; 2 had malignant lymphoma of the small intestine and mesenteric lymph nodes; and 1 had lymphangiosarcoma of the abdominal wall. In 2 cats, chylous ascites was associated with nonneoplastic diseases: 1 cat had severe biliary cirrhosis and an extrahepatic portosystemic shunt; the other had steatitis caused by vitamin E deficiency. Three cats were euthanatized or died at the time of surgery, and 5 cats were euthanatized within 3 months of surgery. One cat with malignant lymphoma responded well to chemotherapy and lived for 14 months after surgery.

Animals↗

Angiosarcoma of the small intestine: a case report and literature review.

A case of primary intestinal angiosarcoma in a 59-yr-old man is reported. The patient had recurrent gastrointestinal bleeding with normal upper and lower gastrointestinal endoscopies, technetium-99m-labeled erythrocyte scan, and angiography. Barium small bowel series and abdominal computerized tomography showed an ileal mass. Pathological examination was consistent with hemangiosarcoma with both solid and vasoformative patterns. Metastatic disease was also identified in the small bowel mesentery, liver, spleen, lungs, and brain. No identifiable underlying or epidemiologic factors have previously been reported to be associated with this rare type of tumor of the gastrointestinal tract. The pertinent literature on gastrointestinal angiosarcoma also is reviewed.

Hemangiosarcoma↗

Residual splenic function in the presence of thorotrast-associated hepatic tumor: case report.

A 50-year-old man had received intravenous colloidal thorium dioxide (thorotrast) 27 years previously. Scintiscans with both 99mTc-sulfur colloid and 131I-rose bengal revealed an extensive intrahepatic defect. At operation, the lesion proved to be an infiltrating hemangiosarcoma. The spleen was small but the chronic internal radiation of the spleen had not completely destroyed the function of radiocolloid uptake. Review of the literature disclosed other cases in which the spleen was still capable of accumulating radiocolloid some years after thorotrast administration. In at least one other instance, radiocolloid uptake was not accompanied by splenic ability to clear Howell-Jolly bodies: a disassociation of splenic functions. The effects of the internal radiation dose to the spleen from thorotrast are discussed and compared with the effects of external radiation. The discrepancy between the effects of the two doses may be related to the high relative biologic effectiveness of the alpha rays from thorotrast compared with gamma-radiation, to nonuniformity of distribution, and to the effects of reticuloendothelial blockade.

Colloids↗

Intravascular papillary endothelial hyperplasia.

Papillary endothelial hyperplasia is a peculiar benign intravascular process that bears a remarkable resemblance to a hemangiosarcoma. In 44 cases of this lesion studied from the files of the Armed Forces Institute of Pathology, the process manifested as a small tumor-like lesion that occurred most frequently in the subcutis of the fingers (14 cases), the head and neck region (ten), and the trunk (seven). Microscopically, the tuft-like or papillary proliferation of endothelial cells was nearly always intimately associated with a thrombus and seemed to represent a peculiar variant of an organizing process. Features that aided in recognition and differential diagnosis from a hemangio-sarcoma included the intraluminal location of the lesion, the absence of tissue necrosis, and the intimate association of the proliferated tuft-like structures with thrombotic material. Follow-up information obtained in 31 cases indicated a benign clinical course despite the sarcoma-like microscopic appearance of this condition.

Adolescent↗

Hemangioendothelioma of bone: a study of 29 cases.

Twenty-nine cases of hemangioendothelioma (H.E.) of the bone have been studied. In addition to the clinical and radiologic features of the tumor, attention was principally paid to the relationships between a tentative histologic grading of malignancy and the clinical course and final outcome of the cases. Three histologic grades are identified: Grade I H.E., Grade II H.E., and Grade III H.E. (or hemangiosarcoma). Grades I and II H.E. are frequently multicentric in the same lower limb. Grade I H.E. has a constantly good prognosis. It may remain stationary for several years even without treatment and it may be cured even by curettage or radiation. Grade II H.E. often has a good prognosis. In one of our cases the initial biopsy was interpreted as being a low grade tumor but the subsequent histology of the local recurrence indicated a Grade III malignancy and the patient died with metastases. Another case was graded II and the patient died with metastases. There are three explanations for this discrepancy: (1) some tumors are malignant in spite of a seemingly low grade histology; (2) low grade and fully malignant areas are present in the same tumor; (3) malignancy may progress in some low grade tumors in the course of time. On the basis of our experience we lean towards the last two possibilities, and therefore recommend histological study of large and multiple sections. Grade III H.E. has a very bad prognosis. The study of H.E. of the bone presents several problems. More information from a larger series of cases is needed to define the value of the histological grading in determining a prognosis, therefore indicating treatment.

Adolescent↗

Mortality and cancer morbidity in workers exposed to low levels of vinyl chloride monomer at a polyvinyl chloride processing plant.

To study whether exposure to low levels of vinyl chloride monomer (VCM) causes increased risk for cancer morbidity and death from ischemic heart disease, a cohort study was performed among 2,031 male workers at a polyvinyl chloride (PVC) processing plant who had been employed for at least 3 months during the period 1945-1980. An almost significantly increased total mortality (SMR = 116, 95% CI 99-136) was found. Deaths caused by violence or intoxication were significantly increased (SMR = 153, 95% CI 109-213), but not deaths from ischemic heart disease (SMR = 100, 95% CI 73-135). A significant increase in total cancer morbidity was observed (SMR = 128, 95% CI 101-161). Respiratory cancers were significantly increased (SMR = 213, 95% CI 127-346). Furthermore, six brain tumors (vs. 2.6 expected) were observed. This increase, however, was not significant (SMR = 229, 95% CI 84-498). No liver hemangiosarcoma was observed. Applying a latency period of greater than or equal to 10 years from start of employment did not change the risk patterns. There were no significant exposure-response associations between exposure estimates for VCM, asbestos, and plasticizers and cancer morbidity.

Adult↗

Phase II trial of gemcitabine in advanced sarcomas.

BACKGROUND: Care for patients with advanced sarcomas is mainly palliative. Gemcitabine, a nucleoside antimetabolite, is an analog of deoxycytidine that has shown antitumor activity in several tumors. The aim of the current study was to determine the clinical activity of gemcitabine in patients with sarcomas. METHODS: The authors evaluated gemcitabine in patients with histologically confirmed sarcomas; one prior exposure to chemotherapy treatment was allowed. Prior radiation was allowed if given to non-indicator lesions. Treatment consisted of gemcitabine 1250 mg/m(2) intravenously over 30 minutes, every week x three, cycles repeated q28 days. RESULTS: Twenty nine of 30 patients were evaluable; one patient refused to initiate study treatment. The mean age was 50 years (range, 22-81 years); 59% were male, and 35% had an Eastern Cooperative Oncology Group performance status of 0 (vs. 1 or 2). Patients were histologically classified as leiomyosarcoma (seven gastrointestinal, four retroperitoneal, two inferior vena caval, three of the extremity, and two uterine), synovial (two patients), malignant fibrous histiocytoma (two patients), fibrosarcoma (one patient), osteosarcoma (two patients), liposarcoma (one patient), hemangiosarcoma (one patient), or giant cell (one patient). Patients received an average of two cycles (range, one to eight). Eighty three percent of patients discontinued treatment due to progression and 14% due to toxicity/refusal. Hematologic toxicities >or= Grade 3 were seen in 32% of patients and consisted of leukopenia and thrombocytopenia. Anorexia (Grade 1/2 in 6 patients, Grade 3 in 1 patient), nausea (Grade 1/2 in 7 patients, Grade 3 in 1 patient), and lethargy (Grade 1/2 in 19 patients) were the most frequently observed nonhematologic toxicities. One patient experienced Grade 3 edema and muscle infarction. A different patient experienced unexplained Grade 3 chest pain. One partial response was observed in a uterine leiomyosarcoma patient lasting at least three months. Overall response rate was 3% (95% confidence interval [CI]: 0-15). Median time -to progression was 2.1 months (95% CI: 1.8-3.0). CONCLUSIONS: The current gemcitabine regimen demonstrated acceptable levels of toxicity, but it failed to produce the number of responses needed to justify expansion of the current study. This regimen is not recommended for advanced sarcomas.

Adult↗

Vectors based on autonomous parvoviruses: novel tools to treat cancer?

Autonomous parvoviruses are small nuclear-replicating DNA viruses. The rodent parvoviruses usually are non- or weakly pathogenic in adult animals, bind to surface receptors which are expressed on most cells, and do not appear to integrate into host chromosomes during either lytic or persistent infections. Interestingly, malignant transformation of the target cells was often found to correlate with an increase in their capacity for amplifying and/or expressing the incoming parvoviral DNA, and is associated with oncolysis, i.e., the selective killing of the infected tumor cells. Moreover, the closely related parvoviruses MVM, H-1 and LuIII efficiently infect human cell lines. This finding makes these parvoviruses promising candidate vectors for therapies that require transient expression of a transduced gene. In particular, parvoviruses may be suitable to target and kill tumor cells and simultaneously deliver appropriate transgenes, e.g., genes coding for immuno-stimulatory factors. Pilot experiments performed in animals to assess whether parvovirus-based vectors carrying the interleukin 2 (IL-2) cytokine gene have reinforced anti-cancer capacity showed that these recombinant viruses suppressed tumor formation more efficiently than viruses devoid of a transgene. Strong anti-cancer effects of recombinant parvoviruses expressing interferon gamma-inducible protein 10 (IP-10) and monocyte chemotactic protein 3 (MCP-3) were also observed against established hemangiosarcomas and melanomas in immuno-competent mice, respectively. Altogether, these data illustrate the enormous potential of recombinant autonomous parvoviruses as anti-tumor agents and give hope of using them against human cancer.

Animals↗

Cyclophosphamide, doxorubicin, and cisplatin combined in the treatment of advanced sarcomas.

Twenty-five patients with evaluable histologically confirmed inoperable metastatic sarcomas were treated once every four weeks with cyclophosphamide, doxorubicin, and cisplatin in doses of 400, 40, and 60 mg/m2, respectively. Cyclophosphamide and doxorubicin were given by rapid intravenous injection followed immediately by cisplatin by slow intravenous infusion (2-6 hr) in 1 liter of 0.45% saline with mannitol added. Leukopenia, alopecia, and vomiting were common side effects and three patients refused further treatment because of vomiting following their initial courses. No drug-related deaths occurred and we removed no one from the study because of toxicity problems. Among the 9 patients who experienced objective tumor regression were 2 of 2 with hemangiosarcoma, 3 of 5 with malignant fibrous histiocytoma, 3 of 5 with osteosarcoma, and 1 of 1 with pleomorphic liposarcoma of bone. Although not therapeutically gratifying, these results appear to be better than any previously observed at our institution.

Adolescent↗

Pharmacokinetics and metabolism of vinyl fluoride in vivo and in vitro.

Vinyl fluoride (VF) is an inhalation carcinogen at concentrations of 25 ppm or greater in rats and mice. The main neoplastic lesion induced in rodents was hepatic hemangiosarcomas, and mice were more sensitive than rats. In a first set of experiments, groups of three rats or five mice were exposed to VF in a closed-chamber gas uptake system at starting concentrations ranging from 50 to 250 ppm. Chamber concentrations of VF were measured every 10-12 min by gas chromatography. Partition coefficients were determined by the vial equilibration technique and used as parameters for a physiologically based pharmacokinetic (PBPK) model. Mice showed a higher whole-body metabolic capacity compared to rats (Vmax = 0.3 vs 0.1 mg/hr-kg). Both species had an estimated Km of < or = 0.02 mg/liter. The specificity for the oxidation of VF in vivo was determined by selective inhibition or induction of CYP 2E1. Inhibition with 4-methylpyrazole completely impaired VF uptake in rats and mice, whereas induction with ethanol (rats only) increased the metabolic capacity by two- to threefold. The pharmacokinetics of VF were also investigated in vitro. Microsomes from rat and mouse liver were incubated in a sealed vial with VF and an NADPH-regenerating system. Headspace concentrations (10-300 ppm) were monitored over time by gas chromatography. Consistent with the in vivo data, VF was metabolized faster by mouse microsomes than by rat microsomes (Vmax = 3.5 and 1.1 nmol/hr-mg protein, respectively). The rates of metabolism by human liver microsomes were generally in the same range as those found with rat liver microsomes (Vmax = 0.5-1.3 nmol/hr-mg protein), but one sample was similar to mice (Vmax = 3.3 nmol/ hr-mg protein). Metabolic rates in human microsomes were found to correlate with the amount of CYP 2E1 as determined by Western blotting and by chlorzoxazone 6-hydroxylation. It is concluded that the greater metabolic capacity of mice for VF both in vivo and in vitro may contribute to their greater susceptibility to tumor formation. CYP 2E1 is clearly the main isozyme involved in the oxidation of VF in all species tested. VF pharmacokinetics and metabolism in humans may depend upon the interindividual variability in the expression level of CYP 2E1. The excellent correspondence between in vivo and in vitro kinetics in rodents improves. substantially the degree of confidence for human in vivo predictions from in vitro data.

Administration, Inhalation↗

Spontaneous neoplasms in control Wistar rats: a comparison of reviews.

Spontaneous neoplasms in 930 control Wistar rats from five carcinogenicity bioassays conducted between 1990 and 1995 were reviewed and compared with review findings in studies between 1980 and 1990. Mean survival at 104 weeks was 55% for males and 60% for females, similar to that of the previous review. A total of 1599 neoplasms was diagnosed in 361 (78%) male and 415 (89%) female rats; 1293 (81%) of these were benign and 306 (19%) were malignant (11% with metastases). Sixty-eight percent of all neoplasms were in endocrine and integumentary systems, similar to 74% seen in the previous review. Most common neoplasms (affecting > 7% of either sex) were pituitary adenoma (34% of males, 50% of females), benign adrenal pheochromocytoma (10% of males, 1% of females), thyroid C cell adenoma (6% of males, 8% of females), mammary fibroadenoma (3% of males, 36% of females), keratoacanthoma (11% of males, 0.6% of females), testicular interstitial cell tumor (11% of males), uterine stromal polyp (16% of females), pancreatic acinar cell adenoma (13% of males, 0.6% of females), and benign thymoma (3% of males, 8% of females). Seventeen neoplasms affecting 2 to 6.9% of either sex included adrenal cortical adenoma, thyroid follicular adenoma, pancreatic islet cell adenoma, pituitary carcinoma, mammary adenoma, mammary adenocarcinoma, fibroma, fibrosarcoma, dermal papilloma, uterine schwannoma, uterine granular cell tumor, pancreatic acinar cell carcinoma, hepatocellular adenoma, lymphoma, granular cell meningioma, renal mesenchymal tumor, and hemangiosarcoma. Remaining neoplasms occurred in fewer than 2% of animals. Mean tumor incidence did not differ significantly between our two reviews. Ratios of benign to malignant neoplasms were similar in both reviews and percentages of survival at 104 weeks were similar. Between the two reviews, greater than threefold increase in frequency of some neoplasms occurred only in males and included keratoacanthomas, pancreatic acinar cell adenomas/carcinomas, and astrocytomas. Frequencies of remaining neoplasms were within twofold or within 10% of previous frequencies. Some neoplasms diagnosed in this review but not in the previous review included cardiac schwannoma, pilomatrixoma, parathyroid adenoma, and prostatic adenoma but incidence was approximately 1% for any one tumor. Based on these reviews, Wistar rats appear to have a predilection to pituitary neoplasms and mammary fibroadenomas (females).

Animals↗

1,3-Butadiene: toxicity and carcinogenicity in laboratory animals and in humans.

1,3-Butadiene is a high production volume chemical used largely in the manufacture of synthetic rubber. The production and use of 1,3-butadiene increased dramatically during World War II with the development of the synthetic rubber industry. Before the 1980s, 1,3-butadiene was not considered to be particularly hazardous to human health; therefore, OSHA established a permissible limit of 1,000 ppm for occupational exposure to this chemical. Results of recent inhalation carcinogenicity studies have demonstrated clearly that 1,3-butadiene is a multiple-organ carcinogen in Sprague-Dawley rats and in B6C3F1 mice. Particularly noteworthy in mice were the early occurrences and extensive development of lymphomas, the induction of uncommon hemangiosarcomas of the heart, and the development of malignant lung tumors at exposure concentrations as low as 6.25 ppm. Because 6.25 ppm was the lowest concentration ever used in a long-term carcinogenicity of this gas, it is likely that lower exposure levels would also cause cancers in laboratory animals. In addition, multiple organ site neoplasia was induced in mice after only 13 weeks of exposure. Two reactive epoxides, 1,2-epoxy-3-butene and diepoxybutane, have been identified as intermediates in the biotransformation of 1,3-butadiene in rats and mice. Metabolism is probably an important factor in the carcinogenicity of 1,3-butadiene, because in vitro mutagenicity of 1,3-butadiene requires metabolic activation, whereas these epoxide intermediates are direct acting mutagens in bacteria and are carcinogens in rats and mice. The metabolism of 1,3-butadiene in rats and mice is linear up to concentrations of at least 1000 ppm. Pharmacokinetic studies on 1,3-butadiene and on 1,2-epoxy-3-butene have revealed certain quantitative differences in metabolic rates between Sprague-Dawley rats and B6C3F1 mice; however, these differences were not of sufficient magnitude to account for the reported different target site carcinogenic responses in these two strains of animals. Thus, additional factors must be involved in distinguishing site specificity in the carcinogenicity of 1,3-butadiene between species. In addition to its carcinogenic effects, 1,3-butadiene is a potent in vivo genotoxic agent to mouse bone marrow cells. Hematologic changes indicative of a partially regenerative anemia were induced in mice at 62.5 and higher concentrations. 1,3-Butadiene is also a reproductive and developmental toxicant. Epidemiology studies of workers employed in the production of 1,3-butadiene or of styrene-butadiene rubber have consistently revealed associations between occupational exposure to 1,3-butadiene and excess mortality due to lymphatic and hematopoietic cancers.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Inhalation↗

Pathogenesis of radiation and virus-induced bone tumors.

Bone cancer can be induced by radionuclides that localize in the skeleton. Histologically, these experimentally induced tumors resemble those found naturally in man; they range from densely ossified osteogenic sarcomas to osteolytic tumors with giant cells and only a small osteoid component. Fibrosarcomas and hemangiosarcomas also can occur in some species. It has not been possible to determine the dose in terms of absorbed energy necessary for bone-tumor induction because radionuclides are not deposited uniformly, and they diminish in amount with time. Also, the precise time when irreversible noeplastic change occurs is not known. With X-rays, however, 500 rads delivered to the endosteal surface of a mouse femur has been shown to cause osteogenic sarcoma. Bone tumors can be induced in mice by viruses. FBJ osteosarcoma virus and RFB osteoma virus were obtained from spontaneous tumors; FBR osteosarcoma virus came from a radiation-induced tumor. All three are RNA viruses with C-type particle morphology, and they are propagated by injecting cell-free extracts of virus-induced tumor. All three are RNA viruses with C-type particle morphology, and they are propagated by injecting cell-free extracts of virus-induced tumor into newborn mice. Interaction studies with bone-seeking radionuclides and these viruses have led to the hypothesis that radiation produces cancer by inactivating a viral inhibitor. There is also evidence of a bone tumor virus in the human disease. The injection of cell-free extracts of human bone cancer into newborn Syrian hamsters has induced a variety of mesenchymal tumors at a rate significantly higher than in the control hamsters. Sixty tumors of this type, including 20 osteosarcomas, 11 fibrosarcomas, and 9 osteomas, have been diagnosed so far in experimental animals; in control hamsters there has been only one, a fibrosarcoma. Immunofluorescence assays and cytotoxicity studies indicated that these hamster tumors carried a human antigen.

Animals↗

Role of liver transplantation in the treatment of unresectable liver cancer.

Resection remains the treatment of choice in liver cancer. In order to avoid liver transplantation in conventionally unresectable tumors ex-situ ("bench" procedure), in-situ and ante-situm resection technique should be preferred whenever feasible. Despite the deficiency of donor organs, a single center experience with 198 patients reveals that liver transplantation continues its role as a therapeutic option for selected patients. At present "favorable" indications for transplantation are International Union against Cancer (UICC) - stage II hepatocellular carcinoma as well as the subtype fibrolamellar carcinoma, uncommon tumors such as epitheloid hemangioendothelioma, hepatoblastoma, and liver metastases from neuroendocrine tumors. Due to unsatisfying results, intrahepatic bile duct-, stage III and IV hepatocellular carcinoma, hemangiosarcoma, and liver metastases from nonendocrine primaries should be excluded from liver transplantation alone. For these advanced tumors, especially in cases of extrahepatic involvement, a combination of liver transplantation and multivisceral resection has been proven feasible. However, a significant improvement in patient survival may only be expected only by currently investigated multimodality treatment protocols which will require further randomized studies.

Bile Duct Neoplasms↗

Morphology and sex-dependent manifestation of nasal tumors in B6C3F1 mice after chronic inhalation of 1,2-dibromo-3-chloropropane.

Groups of 50 B6C3F1 mice of each sex were exposed to air containing of 1,2-dibromo-3-chloropropane at concentrations of 0.6 or 3.0 ppm for 6 hours per day, 5 days per week for 103 weeks. Untreated controls consisted of 50 mice of each sex. All surviving animals were killed at 104 weeks. Adenomas, squamous cell papillomas, adenocarcinomas, squamous cell carcinomas, carcinosarcomas, fibrosarcomas, and hemangiosarcomas of the nasal cavity occurred in male and female mice with dose related trends. Eighty-seven percent of the high dose female mice had nearly twice as many tumors as the high dose males (47%). Fourtynine percent of malignant neoplasms of the high dose female mice infiltrated the brain or metastasized to the lungs. Whereas two animals (4%) of the low dose female mice showed infiltrating carcinomas, no male mice exhibited this feature.

Animals↗