Effect of the antineoplastic agent methotrexate on experimental heterotopic new bone formation in rats.

Heterotopic new bone formation was induced by implanting pieces of demineralized bone matrix in the abdominal wall of 22 growing Sprague-Dawley rats. The animals were divided into three groups and were given, 24 hr after initiation of the bone induction process, a single i.v. injection of methotrexate, 100 or 250 mg/kg body weight, or placebo, followed after 2 hr by leucovorin rescue. A slight and transient arrest in weight gain was noted in the methotrexate-treated animals. New bone formation during 3 weeks after implantation was analyzed by the amount of ash in implants, and as a measure of bone formation at the end of the experiment, short-time incorporation of 45Ca and [3H]proline was used. The ash content of implants was reduced by 56 and 68% in the two methotrexate groups. Uptake of both nucleotides was also greatly reduced in heterotopic bone, whereas metaphysial and diaphysial tibia and teeth were not affected. The results indicate a pronounced inhibition of methotrexate on bone induction, persisting for at least 3 weeks. Methotrexate reduces the bone-forming potential, with possible consequences for the success of limb-saving surgery and fracture healing.

Influence of human alpha-interferon on four human osteosarcoma xenografts in nude mice.

Growth-inhibiting effects of human alpha-interferon (HuIFN-alpha) were investigated in four human osteosarcoma xenografts in nude mice. In addition to effects on growth, the HuIFN-alpha treatment was evaluated by histological examination and DNA flow cytometric analysis. Daily doses of 2 X 10(5) IU HuIFN-alpha completely arrested the growth of two osteosarcoma xenografts and partially inhibited one, whereas 1 X 10(6) IU/day were necessary to arrest the growth of the fourth. Growth inhibition was reversible and tumor size independent. The histological appearance, including mitotic indices, and S-phase proportions were unchanged in three xenografts. The mechanism of the HuIFN-alpha-induced growth inhibition of these three xenografts was therefore not considered to be a direct antiproliferative effect, but rather due to increased cell loss and/or increased cell cycle time. The modal DNA value of one xenograft was changed from aneuploid to diploid during HuIFN-alpha treatment. Histologically, these xenografts were partly replaced by normal appearing bone and bone marrow. The S-phase proportion was also reduced in these xenografts, implying that HuIFN-alpha can also have a direct antiproliferative effect.

Adjuvant interferon treatment of human osteosarcoma.

This paper updates the results of the clinical trial to examine the efficacy of exogenous leukocyte interferon therapy as adjuvant treatment for osteosarcoma. So far the incidence of metastases is lower and the survival rate is better for the interferon-treated group than for the concurrent control group. The number of treated patients is too small at present to allow proper statistical calculations to be made.

Adjuvant interferon treatment in human osteosarcoma.

An update of the adjuvant trial on osteosarcoma in Sweden comparing patients receiving natural interferon (IFN) alpha with a high-dose chemotherapy group and a nonadjuvant group is presented. The overall survival for the IFN group is 49%, for the chemotherapy group 54%, and for the nonadjuvant group 35%. Trial evaluation was complicated by group differences with respect to various clinicopathologic features of prognostic significance. The role of IFN in the treatment of osteosarcoma can still not be established.

The age of osteosarcoma patients is increasing. An epidemiological study of osteosarcoma in Sweden 1971 to 1984.

We conducted an epidemiological study of osteosarcoma in Sweden from 1971 to 1984 to investigate whether the typical features of the disease had changed. Of 294 osteosarcoma patients reviewed, 249 had primary skeletal tumours, and for these the mean annual incidence was 2.1 per million, without any clear trend over time. The mean male/female ratio for the period was 1.6 again with no consistent pattern over time; nor was there any significant change in the distribution of tumours according to location. The only feature which showed a significant change over the 14-year period was the mean age of the patients, being at its lowest (19 years) in 1972 and at its highest (40 years) in 1981. Excluding the 22 patients with craniofacial tumours, the remaining 227 also showed a significant increase in mean age. Analysis of the annual age distribution disclosed an increasing fraction of patients older than those in the classical age peak between 10 and 29 years. A large number of trials have shown improved survival in osteosarcoma over the last 15 years, which has been attributed mainly to adjuvant chemotherapy. The change we have observed in age distribution should also be taken into account in the evaluation of the results of treatment; it may be that older patients have a better prognosis.

Staging of soft-tissue sarcomas. Prognostic analysis of clinical and pathological features.

In a retrospective study of all 137 patients with soft-tissue sarcoma treated by surgery between 1972 and 1984, the clinical course was related to several host and tumour features, including the Surgical Staging System of Enneking, Spanier and Goodman (1980). Only patients free from metastasis with untreated primary lesions on admission were included. According to the Surgical Staging System, nine tumours were IA, 18 IB, 38 IIA and 72 IIB. Only 12 patients underwent amputation; 125 were treated by local surgery. The mean follow-up time was ten years (minimum five). For the whole series the probability of seven-year survival was 0.65; 42 patients (31%) died from tumour disease. All these had metastases and 24 also had local recurrence. The local recurrence rate was 36%. Multivariate analysis identified large tumour size and high histological grade as significant risk factors for metastatic disease and tumour-related death. Sex, age, tumour site, surgical margin and local recurrence showed no correlation with survival. The prognostic contribution of compartmentality was virtually nil. Histological grade combined with tumour size was found to give better prognostic information than that obtained by the Surgical Staging System.

The effect of biopsy on survival of patients with osteosarcoma.

A retrospective study of patients with osteosarcoma was undertaken to determine whether there was a relationship between biopsy and survival. Fifty-seven patients treated at the Karolinska Hospital, Stockholm, between 1938 and 1959 were included in this study, all of whom were less than thirty years old, had a metaphysial osteosarcoma in a long bone but had no pulmonary metastases at the time of diagnosis; all were treated by amputation. No clinical variants of osteosarcoma were included. Twenty-four of the fifty-seven patients had an amputation without a prior biopsy; the others had biopsies before amputation. These two groups were fairly closely matched in age, sex, site and size of tumour, and in the level of amputation; some patients in each group received radiation before operation. Evaluation of these two groups of patients revealed that the performance of a biopsy, with or without a delay of not more than thirty days between the biopsy and the definitive operation, had no adverse effect on survival.

[The results of a combination of interferon and selective surgery in the treatment of osteosarcoma (author's transl)]. / Traitement de l'ostéosarcome par l'interféron et la chirurgie différenciée.

Since 1971, Interferon has been used by the authors in the treatment of 46 consecutive cases of osteosarcoma. Two thirds of the cases were treated by amputation, the remainder being treated by resection followed by grafting or a prosthesis. No case was treated by radiotherapy or chemotherapy. Before 1971, the survival rate was 15 p. 100; in contemporary cases treated without Interferon, the rate of survival was 30 p. 100. In the present series the rate of survival was 50 p. 100 after 5 years. It is concluded that Interferon seems to have a positive action. The selection of cases which can be treated by local resection is difficult.

Treatment of osteosarcoma by interferon and differentiated surgery.

Since 1972, all cases of osteosarcoma (48 patients) at the Karolinska Hospital in Stockholm have been treated by leukocyte interferon. It has been administered by intra-muscular injections with a dosage of 3 million standard interferon units daily for one month and thereafter 3 times weekly for a further 17 months. Thirty-two patients were subjected to amputation or disarticulation, but in 16 cases local surgery has been resorted to and the defect after tumour resection has been replaced by autogenous bone grafting or endoprostheses. In 5 of 16 locally treated cases, local recurrence occurred and amputation was performed. Four of the patients later on succumbed from metastases. The selection of cases which can be treated by local resection is difficult. In the present series, the rate of survival was 58% after 5 years. Before 1972 (historical group) the survival rate was 14%. The corresponding - 5 - year survival figure for the contemporary group treated without interferon is 33%. Although the 58% survival rate seems to represent an effect of interferon on osteosarcoma, no statistically significant conclusions can be drawn.