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An animal model for human osteosarcoma.

Osteosarcomas formed in antilymphocyte serum (ALS)-treated hamsters when 2x10(6) TE-85 human osteosarcoma cells (maintained in tissue culture) infected with M-MSV (RD-114) virus were injected adjacent to the femur or the scapula; undifferentiated sarcomas formed when 1 x 10(6) cells were injected subcutaneously. Tumors were palpable 10 to 14 days after the cells were injected and grew progressively until the animals died (mean survival time was 30 days). All animals had pulmonary metastases. Neither the subcutaneous sarcomas nor the metastases contained bone or osteoid; however, the osteosarcomas adjacent ot the femur and scapula contained collagen, osteoid and calcified bone when observed by light and electron microscopy. These results indicate that the TE-85-M-MSV cell-ALS hamster system is an animal model for the study of osteosarcomas of human cell origin.

Animals↗

Adjuvant chemotherapy for osteosarcoma.

From this review of chemotherapy trials, several observations can be made. Osteosarcoma is a complex disease involving multiple histologies, each with a different prognosis. Prognostic factors that have been shown to be important include anatomic location of the primary tumor, stage at presentation (patients with metastatic or local recurrent disease fair far worse than those with primary disease), age at onset (children fair worse than the teenager with osteosarcoma), and location within the extremity (patients with more distal tumors fairing better than patients with more proximal tumors). There is convincing evidence for the efficacy of chemotherapeutic agents such as methotrexate in high doses (at least 8 g/m2 for adults, 12 g/m2 for children), Adriamycin, and cisplatin. The combination of Adriamycin and cisplatin appears to be more beneficial relative to either one of these agents alone. The efficacy of the combination of BCD as a triple-drug regimen, although useful in several different trials, has not been convincingly shown. Finally, from several of the recent randomized trials, it appears, that chemotherapeutic regimens containing an Adriamycin and cisplatin combination appear to be superior to those that do not include this combination. However, these observations are made from a historical perspective and have not been conclusively proven by randomized prospective investigations. The observations concerning the natural history of the disease and the activity of various chemotherapeutic agents suggest certain clinical practice algorithms. Essential staging procedures would include a bone scan looking for multifocal or metastatic disease, and CT scans of the chest looking for metastases to the lung. From all studies, it is apparent that surgery is mandatory for the primary tumor and should be an integral portion of all treatment methods. Chemotherapy should be considered for all patients with osteosarcoma, and the essential drugs in the regimen appear at present to minimally include high-dose methotrexate, Adriamycin, and cisplatin. It would also appear from several of these reports that not only is the adjuvant use of these chemotherapeutic agents indicated, but that the preoperative use of these agents has had significant advantages. The neoadjuvant chemotherapy begins the essential systemic chemotherapy at a very early stage, allows histologic assessment of treatment effect, permits altering drug regimens postoperative, and in many reported trials has allowed less than amputative surgery (limb salvage) to be performed. Finally, close follow-up of patients with osteosarcoma has therapeutic value.(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗

An osteosarcoma cell and matrix retained morphogen for normal bone formation.

Histophysiology, ultrastructure, chemical analyses of transplants and implants of Dunn and Ridgway mouse osteosarcomas demonstrate that tumorigenesis is a manifestation of deranged morphogenesis in developing mesenchymal cell populations. The end product of development is defective, incompletely calcified, disorganized bone without any inclusions of bone marrow tissue. When Dunn osteosarcoma is freeze-dried and then implanted, the tumor is resorbed and replaced by deposits of normal cartilage, bone, and bone marrow. Freeze-dried Ridgway osteosarcoma is replaced only by a fibrous connective tissue scar. Disaggregated Dunn tumor osteoblasts synthesize a trypsin-labile collagenase-resistant cell surface localized bone morphogen. Tumor matrix stroma, prepared by sequential chemical extraction of soluble non-collagenous proteins also contains significant quantities of the same bone morphogen. Tumor tissue pulverized to particle size as small as 44 micrometer3 transmitted bone morphogen more rapidly than intact tumor tissue. The total tumor cell and stroma mediated bone morphogen produces three times more normal bone than normal cortical bone matrix. Our working hypothesis is that a normal bone morphogenetic polypeptide (BMP) is synthesized by Dunn osteosarcoma cells and retained by the tumor matrix stroma. Neither the mechanism of transmission nor the mesenchymal cell receptor sites of BMP are known.

Alkaline Phosphatase↗

Alkaline phosphatase measurements of paired normal and osteosarcoma tissue culture lines obtained from the same patient.

Markedly different levels of alkaline phosphatase production have been found in paired osteosarcoma cells and normal skin fibroblasts grown in tissue culture from 12 patients with osteosarcoma. In all cases, the osteosarcoma line contains significantly more alkaline phosphatase than does the paired normal line from that same patient. These criteria may be useful in distinguishing osteosarcoma from normal fibroblast overgrowth in tissue culture.

Alkaline Phosphatase↗

Provirus integration and myc amplification in 90Sr induced osteosarcomas of CF1 mice.

In mice, endogenous retroviruses are known to be activated during the course of radiation osteosarcomagenesis. Using the Southern blotting procedure, we have studied the presence of somatically acquired proviruses in genomic DNA isolated from seven primary 90Sr induced osteosarcomas and one osteosarcoma cell line, 0-127a1, of the CF1 mouse strain. Specific hybridization probes demonstrated the presence of newly integrated ecotropic proviruses in four primary tumors. Probably, clonally integrated proviruses were present at distinct locations in different subpopulations of tumor cells, reflecting tumor heterogeneity. Genomic DNA isolated from cultured osteosarcoma cells contained different additional MCF-related proviruses. No proviruses were found integrated in the vicinity of c-myc, but a large domain containing the complete c-myc gene was found amplified in one primary tumor (greater than 22 kbp) and in 0-127a1 cells (greater than 39 kbp). Our data suggest that activated retroviruses are not essential for the development of radiogenic osteosarcomas in CF1 mice, but they might be responsible for the deregulated expression of a growth promoting gene in some bone tumor cells.

Animals↗

Hypoxanthine:guanine phosphoribosyltransferase activity in xenografts of human osteosarcoma.

It has recently been reported that human osteosarcomas may lack the purine salvage pathway enzyme, hypoxanthine:guanine phosphoribosyltransferase (EC 2.4.2.8). We have established a quantitative assay for measurement of this enzyme in human osteosarcoma xenografts with analysis of products by thin-layer chromatography. Nucleotidase or phosphatase activity was readily detected and could be abolished by preheating cytosol at 60 degrees C for 10 min and performing the assay at pH 10. Alternatively, the use of 25 mM NaF at pH 7.4 also inhibited this activity. The pH optimum for this enzyme in red blood cell sonicates and tumor cytosols was pH 10. All six human osteosarcoma xenografts contained hypoxanthine:guanine phosphoribosyltransferase activity ranging from 0.97 to 4.06 nmol/min/mg of protein at pH 7.4. Control human red blood cell sonicates demonstrated activity of 0.83 nmol/min/mg of protein. These data demonstrate that human osteosarcoma xenografts contain substantial activities of this purine salvage pathway enzyme.

Animals↗

Osteosarcoma in cats: 22 cases (1974-1984).

Osteosarcoma was diagnosed in 22 cats. Diagnosis was based on results of physical, radiographic, and histologic findings. Fifteen tumors arose from the appendicular skeleton, 4 from the skull, 2 from the pelvis, and 1 from a rib. Radiography revealed that in 14 of 15 cats (93%) with appendicular tumors, the lesion was metaphyseal, primarily lytic, with a "moth-eaten" appearance; absence and presence of periosteal new bone formation were associated with the tumors in 12 and 3 cats, respectively. The remaining 7 cats had axial tumors that were characterized by the presence of periosteal new bone formation in addition to bony lysis. Of the 15 cats with appendicular tumors, 12 were treated by amputation and 3 were euthanatized at the time of diagnosis. Of the cats undergoing amputation for treatment of their appendicular tumors, 6 cats were still alive 64 months after surgery (range, 13 to 64 months); the median survival time of the 5 cats (1 cat was lost to follow-up evaluation) that died was 49.2 months (range, 1 to 122 months). Four of 12 cats (33%) survived greater than or equal to 5 years after diagnosis. Of the cats with axial tumors that were not euthanatized at the time of diagnosis (6 of 7), the median survival time was 5.5 months. Based on these findings, we concluded that cats with appendicular osteosarcoma have a better prognosis than those with axial osteosarcoma, and that amputation is a viable treatment for cats with appendicular osteosarcoma.

Animals↗

[Rationale of preoperative chemotherapy of osteosarcoma].

The rationale of preoperative chemotherapy for osteosarcoma requires: eradication of microscopic metastatic foci which have already occurred in many patients with osteosarcoma, determination of a more effective form of postoperative adjuvant chemotherapy and easier and safer limb-salvage procedures through clearer marginal definition with reduction of primary lesions. In this paper, chemotherapeutic effects on the 5-year survival rate were analyzed for 49 patients with primary non-metastatic osteosarcoma of the extremities treated with radical surgery. The efficacy of preoperative chemotherapy was assessed in 11 cases of osteosarcomas treated with systemic chemotherapy as a preliminary study. As to the 5-year cumulative survival rate, the systemic group (20 cases) showed a level of 56.7%, which was significantly higher (p less than 0.05) than the figure of 13.8% in a historical retrospective group (29 cases). In assessing the effective tumor response to preoperative chemotherapy, a close correlation between the tumor necrotic ratio and the ratio of decrease of serum alkaline phosphatase was revealed. Seven (63.6%) of 11 cases showed correlation of the tumor necrotic ratio with the ratio of decrease of serum alkaline phosphatase. The tumor necrotic ratios calculated were relatively definite (50-60%) in the CDDP group (3 cases), varied (10-70%) in the HDMTX group (4 cases), and low (less than 40%) in the ADR group (4 cases), regarded as a control group in further studies.

Adult↗

[Functional evaluation of the preserved limb following resection of osteosarcoma and malignant bone tumors].

Studies were done on functional evaluation of limb salvage for malignant bone tumors treated in our hospital (32 cases), and for osteosarcomas treated in 21 institutes throughout Japan (104 cases). These two groups were compared in order to clarify the characteristics and problems of limb-saving surgery for osteosarcoma. The international functional evaluation system was used and scores given according to the grading, i.e. excellent 5; good, 3; fair, 1; poor; 0. All cases were statistically studied by grouping of the term of follow-up, i.e., less than 2 years, 2 to 3 years, and over 3 years. As a result, the most decisive factor in the evaluation was found to be motion, which was mainly correlated with the degree of resection and the method of reconstruction. Characteristics in osteosarcoma were that the 2-3-year group acquired the highest score, although, in the 3-years and over group, evaluation scores fell because of prosthesis trouble. Emotional acceptance was lower in osteosarcoma patients. It was especially though that since limb-saving has a major premise of life-saving, saving of a limb should be considered from the viewpoint of life-usefulness.

Activities of Daily Living↗

[Regional isolation perfusion with cisplatinum in dogs with osteosarcoma of an extremity].

In the treatment of osteosarcoma, it is possible to differentiate between systemic therapy and local regional treatment. Systemic treatment of human patients with osteosarcomas consists in adjuvant chemotherapy. This has considerably improved the prognosis in these cases. The primary object in local regional treatment is to prevent local recurrences and to preserve function. As regards extremities, the aim is to preserve the limbs. In the present investigations, the value of regional chemotherapy by isolated regional perfusion with cis-platinum to dogs is studied. This approach was based on the hypothesis that considerable necrosis of tumours may be produced after perfusion with cis-platinum, thus making extremity-saving surgery possible. Isolated regional perfusion with cis-platinum (30 mg/litre of extremity volume) was performed in nine dogs with osteosarcomas of an extremity. A marked effect on the tumour was detectable on the basis of clinical, radiological and histological parameters. In the opinion of the present authors, regional perfusion with cis-platinum may contribute to extremity-saving treatment of osteosarcomas in dogs and human subjects. However, further studies will be required in order to achieve more adequate quantitation an improvement of local effects. In view of the synergy with cis-platinum, the latter may possibly be attained by the addition of hyperthermia (temperatures above 41.5 degrees C).

Animals↗

High-dose methotrexate in osteosarcoma--Mayo Clinic studies.

While high-dose methotrexate (HDMTX) is active against some osteosarcomas, its efficacy as a single agent in the treatment of metastatic disease has not been uniformly demonstrated. Furthermore, the results of a limited randomized study comparing HDMTX-vincristine with observation alone as primary adjuvant treatment do not support the thesis that HDMTX has been an essential factor in the recently improved control of primary osteosarcoma. Despite this uncertainty concerning the specific contribution of methotrexate to these results, multidrug regimens containing this agent do appear to improve the prognosis of patients with primary osteosarcoma. Regimens which exclude HDMTX reasonably may be studied in the adjuvant treatment of primary osteosarcoma.

Combined Modality Therapy↗

[Significance of surgical adjuvant chemotherapy in osteosarcoma].

The primary site of the metastasis of osteosarcoma is the lung. More than 90% of patients have died of pulmonary metastasis in one to two years. Control of osteosarcoma depend upon the prevention of its pulmonary metastasis. The introduction of chemotherapy consisting mainly of Adriamycin, high-dose methotrexate with Leucovorin rescue and Cisplatinum, dramatically improved the prognosis of osteosarcoma. In the past, when systemic chemotherapy was not available, the five-year survival rate was around 19%. In patients who receive chemotherapy with the current combination of chemotherapeutic agents (ADM, HD-MTX, VCR, CPM, CDDP), the incidence of pulmonary metastasis was low, and the five-year survival rate increased to 65%. In patients who receive chemotherapy, pulmonary metastasis may be either delayed, with a single metastasis appearing after termination of treatment (late isolated type), or early and multiple, emerging in reaction to treatment (early multiple type). It is generally accepted that post-operative chemotherapy can inhibit pulmonary micro metastasis and prove to be of great significance in improving the survival rate of patients with osteosarcoma of extremities and achieve limb salvage operation. On the other hand, effective control of the side effects of drug administration such as nausea, vomiting, alopecia, cardio (ADM) and renal (CDDP) toxicity and bone marrow suppression, is a problem that must be solved as soon as possible.

Adolescent↗

Osteosarcoma in a 14 month old female child.

A case of osteosarcoma in a 14 month old girl is reported. The child presented with a history of difficulty in standing for 2 months and x-rays revealed an osteolytic lesion in the upper third of the femur associated with widening of bone and periosteal reaction. Osteosarcoma was diagnosed by biopsy. Treatment was refused and the child died 13 weeks later. Only one other case of osteosarcoma in a child as young as 14 months has been reported. A review of literature showed 22 cases of osteosarcoma in children aged 5 years or younger.

Age Factors↗

Hemothorax associated with telangiectatic osteosarcoma in a dog.

Hemothorax in a dog was attributed to bleeding from an intrathoracic mass attached to the sixth through the tenth ribs. The mass contained numerous cavernous, blood-filled spaces as well as bands of osteoid and occasional foci of osseous tissue. The diagnosis was telangiectatic osteosarcoma. Telangiectatic osteosarcoma is an uncommon variant of osteosarcoma. Cavernous, blood-filled spaces and paucity of bone are important histologic features. Metastasis was described in one of the seven telangiectatic osteosarcomas reported in dogs, and none was found in this case.

Animals↗

[Isolation and characterization of retroviruses expressed in murine osteosarcomas induced by 90Sr].

The induction of osteosarcomas with 90Sr in CF1 mice is associated with the expression of ecotropic type-C RNA viruses devoid of sarcomatogenic activity. In contrast, the FBR murine osteosarcoma virus complex, isolated from a 90 Sr-induced osteosarcoma of a X/Gf mouse [M. Finkel et al. (1)], causes the rapid appearance of osteosarcomas in newborn mice and transforms fibroblasts in vitro. The transforming capacity of FBR murine sarcoma virus has been associated as an oncogene homologous to v-fos.

Animals↗

[An experimental model of osteosarcomas in rats ].

Satisfactory experimental models for preclinical prediction in cancerology must answer the following criteria: reproducibility of the method used for inducing tumors; clinical, pathological and kinetic similarity with the corresponding human tumors. We have developed a model of osteosarcoma locally induced by insoluble radioactive cerium chloride (144Ce CI3) in Sprague Dawley rats. This method yields over 80% of bone tumors at the injection site, of which approximately half are histologically similar to human tumors. These tumors double their volume fairly slowly (in approximately 20 days); lung metastases occur both early and frequently (80% of animals). A transplantable tumor was developed from an induced osteosarcoma and adapted to the Curie strain. Transplantation in the bone, next to the bone, or under the skin is followed by widespread metastatic dissemination. The kinetics and histological features of the primary tumor are maintained. Tumor 85 strontium uptake is similar to that seen in human osteosarcomas. These new models of osteosarcomas are being used for evaluating new cancer chemotherapeutic agents and interferon, etc.

Animals↗

Osteosarcoma of extragnathic craniofacial bones.

Osteosarcomas of extragnathic craniofacial bones--those bones of the skull excepting the jaw bones--are rare lesions, constituting fewer than 2% of all osteosarcomas. In our series of 21 patients (12 male and 9 female), the ages ranged from 6 to 77 years, and 10 patients were in the third or fourth decade of life. At least six patients had predisposing conditions: Paget's disease of bone in three and prior regional irradiation in three. Most of these tumors were high-grade lesions, and most were extensive when treated. There were 11 osteoblastic, 6 fibroblastic, and 1 small cell variant; 2 lesions had features resembling malignant fibrous histiocytoma. One tumor, originally interpreted as grade 4 osteosarcoma, was unavailable for variant classification. Surgical removal, irradiation, and chemotherapy were used in treatment, alone or in combination. Only two patients survived 5 years, and one of these patients died of her disease after 65 months. Almost half of our patients died within 1 year after diagnosis. The one long-term survivor (12 years) underwent a radical surgical procedure when her tumor was small; this was the only patient in this series who had a low-grade lesion. Because of the characteristics described, osteosarcoma of extragnathic craniofacial bones must be considered a distinct disease.

Adolescent↗

[Preservation of the affected limbs in the treatment of osteosarcoma in children].

The pre-operative radiotherapy and systemic chemotherapy is effective in reducing the size of tumor and making the tumor resectable. The results achieved with systemic chemotherapy are ultimately reflected in improved survival. Moreover, limb-saving procedure in the treatment of osteosarcoma has become possible with rationality in carefully selected patients. Sixty-seven patients with osteosarcoma within a range of 5 to 27 years of age were treated at Chiba Cancer Center Hospital in the recent 12 year-duration. Seventeen of 67 patients underwent en bloc resection for osteosarcoma of the femur, (12 patients) and the tibia (5 patients). No patients had evidence of local recurrence of the tumor and overall 15 patients are alive without distant metastasis after 9 to 120 months follow-up. Based on the effective chemotherapy schedule, the limb salvation in the treatment of osteosarcoma is most desirable if it is indicated without risk of decreased radicality of the treatment.

Adolescent↗