Concomitant tumour resistance in patients with osteosarcoma. A clue to a new therapeutic strategy.

Concomitant tumour resistance (CTR) is a unique phenomenon in which animals harbouring large primary tumours are resistant to the growth of smaller metastatic tumours by systemic angiogenic suppression. To examine this clinically, in ten patients with osteosarcoma, we investigated the effects of removal of the primary tumour on the development of pulmonary metastases, the systemic angiogenesis-inducing ability and the serum levels of several angiogenesis modulators. We found that removal of the primary tumour significantly elevated systemic angiogenesis-inducing ability in five patients who had post-operative recurrence of the tumour. Post-operative elevation of the angiogenesis-induced ability was suppressed by the addition of an angiogenic inhibitor, endostatin. Also, primary removal of the tumour decreased the serum levels of vascular endothelial growth factor and endostatin. These findings suggest, for the first time, the presence of CTR in patients with osteosarcoma for whom post-operative antiangiogenic therapy may be used to prevent the post-operative progression of micrometastases.

Preoperative cisplatin for initial treatment of limb osteosarcoma: its local effect and impact on prognosis.

PURPOSE: The significance of preoperative cisplatin (CDDP) as a single agent has not been assessed in terms of its effect on prognosis. The purpose of this multi-institution study was to assess the local effect of preoperative CDDP as a single agent as well as its impact on the prognosis of limb osteosarcoma. PATIENTS AND METHODS: The study group comprised 44 patients with stage IIB limb osteosarcoma who were treated with single-agent CDDP as initial preoperative chemotherapy. Two to five courses of CDDP (mean 2.4 courses) were administered intravenously and/or intraarterially as an initial preoperative treatment. The mean dose of CDDP was 3.0 mg/kg (2.5-3.4 mg/kg). The effect of the treatment was evaluated clinically and histologically. RESULTS: The clinical and histological response rates to preoperative CDDP were 56.8% and 47.6%, respectively. The survival rate was 59.1% among all patients in the study, 64.0% among those with a grade III or IV clinical response, and 52.6% among those with a grade I or II clinical response, with no significant differences between the groups. The survival rate was 70% among patients with a grade III or IV histological response, and 54.5% among those with a grade I or II histological response, with no statistical differences between the groups. CONCLUSIONS: We consider that CDDP is a useful chemotherapeutic agent for preoperative induction therapy for osteosarcoma because of the excellent local effect observed. Good responders to preoperative CDDP showed a better survival rate, but a correlation between the local response to CDDP and the survival rate was not demonstrated statistically. Systemic multidrug chemotherapy should follow preoperative CDDP to diminish the microscopic foci of metastatic disease.

Increased pre-therapeutic serum vascular endothelial growth factor in patients with early clinical relapse of osteosarcoma.

To investigate the clinical significance of circulating angiogenic factors, especially in association with early relapse of osteosarcoma, we quantified pre-therapeutic levels of vascular endothelial growth factor, basic fibroblast growth factor and placenta growth factor in the sera of 16 patients with osteosarcoma using an enzyme-linked immunosorbent assay. After a 1-year follow-up, the serum level of angiogenic factors was analysed with respect to microvessel density of the biopsy specimen and clinical disease relapse. The serum vascular endothelial growth factor levels were positively correlated with the microvessel density with statistical significance (P=0.004; Spearman rank correlation) and also significantly higher in seven patients who developed pulmonary metastasis than the remaining nine patients without detectable disease relapse (P=0.0009; The Mann-Whitney U-test). In contrast, the serum levels of basic fibroblast growth factor or placenta growth factor failed to show significant correlation with the microvessel density or relapse of the disease. Although there was no significant correlation between serum vascular endothelial growth factor levels and the tumour volume, the serum vascular endothelial growth factor levels were significantly higher in patients with a vascular endothelial growth factor-positive tumour than those with a vascular endothelial growth factor-negative tumour. These findings suggest that the pre-therapeutic serum vascular endothelial growth factor level reflects the angiogenic property of primary tumour and may have a predictive value on early disease relapse of osteosarcoma.

Development of acute myeloid leukemia after chemotherapy for osteosarcoma.

The current study describes two patients with osteosarcoma who had acute myeloid leukemia develop after treatment with multiagent chemotherapy. The incidence density for the chemotherapy protocol was 129.8 per 10,000 person-year of followup. Karyotype analysis of 16 reported patients (including the current two patients) indicated that most leukemias after treatment of osteosarcoma correlated with the use of topoisomerase II inhibitors, such as doxorubicin. The deoxyribonucleic acid-damaging activity of doxorubicin reinforced by the use of alkylating agents is highly suspected as a causative event in the development of leukemia after treatment of osteosarcoma. As the next step in the development of treatment for patients with osteosarcoma, the type and intensity of treatment must be evaluated to minimize possible leukemogenic effects without compromising the potential for cure.

Resection arthrodesis of the knee with a vascularised fibular graft. Medium- to long-term results.

We present the results in 12 patients of arthrodesis of the knee using a vascularised fibular graft after resection of a malignant bone tumour. At a mean follow-up of 95 months (60 to 178) all patients were free from disease although 11 had had at least one complication, with stress fracture of the graft in five patients, nonunion in two and deep infection requiring above-knee amputation in one. Despite the high rate of complications, satisfactory results can be obtained using this technique. Careful preoperative counselling is required.

Reconstruction and limb salvage after resection for malignant bone tumour of the proximal humerus. A sling procedure using a free vascularised fibular graft.

We assessed the intermediate functional results of eight patients after wide resection of the proximal humerus for malignant bone tumour. We used a free vascularised fibular graft as a functional spacer and a sling procedure to preserve passive scapulohumeral movement. Scapulohumeral arthrodesis was not carried out. Five patients had osteosarcoma, two achondrosarcoma and one a malignant fibrous histiocytoma of the bone. The mean duration of follow-up was 70 months (median, 76) for the seven patients who were still alive at the time of the latest follow-up. One patient died from the disease 12 months after surgery. There were no local recurrences. The functional results were described and graded quantitatively according to the rating system of the Musculoskeletal Tumour Society. Our results were satisfactory with regard to pain, emotional acceptance and manual dexterity. Function and lifting ability were unsatisfactory in two patients. One patient had delayed union between host and graft, but this united after six months without further surgery. Radiographs of the shoulder showed absorption or collapse of the head of the fibula in four of the eight patients and a fracture in another. No functional problems related to absorption or fracture of the head of the fibula were noted. There was no infection or subluxation of the head. We conclude that this is a reasonably effective technique of limb salvage after resection of the proximal humerus.

A preliminary report of neoadjuvant chemotherapy NSH-7 study in osteosarcoma: preoperative salvage chemotherapy based on clinical tumor response and the use of granulocyte colony-stimulating factor.

Eleven patients with high-grade osteosarcoma of an extremity were treated with neoadjuvant chemotherapy with NSH-7 protocol. NSH-7 is a refinement of the T-12 Rosen protocol. Preoperative chemotherapy is initiated with a doxorubicin (ADM) and high-dose methotrexate combination. If the primary tumor progresses after the first cycle, the preoperative chemotherapy is switched to a combination of cisplatin and ADM. Postoperative adjuvant chemotherapy was selected based on histological response of the primary tumor. In addition, recombinant human granulocyte colony-stimulating factor was used to prevent leukocytopenia and to increase the dose intensity of the chemotherapy. In 1 patient, preoperative chemotherapy was switched to salvage treatment. Of the 156 courses given, there were 10 delays and 4 dose reductions. Leukocytopenia accounted for only 1 delay. All 11 patients completed the chemotherapy and 5 patients were fully able to tolerate the protocol without delay or dose reduction. Nine patients remained alive and continuously free of disease at an average follow-up of 35 months. The rate of continuous disease-free survival at 3 years was 81%, which was significantly better than that of the T-12 study of our group. These observations suggest that the NSH-7 protocol is a safe and effective treatment regimen for osteosarcoma.

Hyperplastic callus formation in both femurs in osteogenesis imperfecta.

A 3-year-old boy with osteogenesis imperfecta had hyperplastic callus formation in the right femur, without preceding trauma or fracture. Radiologically, this bony mass in the femoral shaft mimicked osteosarcoma. Open biopsy showed that it was benign and suggested hyperplastic callus formation. Seven months after the biopsy, the hyperplastic callus had practically vanished. A similar process developed in the left femur 1 year later, also without fracture.

A prepayment scheme for hospital care in the Masisi district in Zaire: a critical evaluation.

In most developing countries, government funding allocated to the health services is not sufficient to allow these services to provide appropriate health care accessible to all. Consequently, community financing has received much more attention in recent years and innovative schemes are being explored throughout the developing world. Risk-sharing schemes, like prepayment, are interesting because of their potential redistributive effects. At the end of the eighties, a prepayment scheme for hospital care was experimented with in the Masisi health district in Eastern Zaire. In the present paper, the experiment is described in a chronological way and the results are analyzed and discussed in detail. Although this particular case-study was not successful, it yields important lessons concerning the design, implementation and evaluation of prepayment schemes for hospital health care in developing countries. More specifically, phenomena like adverse selection and moral hazard are discussed. Finally, conditions for success of similar experiments are discussed. These conditions relate mainly to the organization pattern of the district health services system. The Masisi experiment is a nice illustration of the fact that prepayment is not a 'magic bullet': the lessons drawn from it may be of relevancy to health planners intending to implement hospital prepayment schemes in similar settings.

Comparison of magnetic resonance imaging and computed tomography in the local assessment of osteosarcoma.

We have compared the value of magnetic resonance imaging (MRI) with computed tomography (CT) in assessing the extent and the localization of osteosarcomas. Twenty patients were examined by both systems, and the results related to the clinical and histological findings. While both investigations are valuable, MRI may be more useful for defining the local extent of an osteosarcoma.

[Adjuvant chemotherapy of osteosarcoma].

Osteosarcoma is the one of the tumors that's prognosis have been improved dramatically by the introduction of chemotherapy consisting mainly of adriamycin, high-dose methotrexate with Leucovorin rescue and cisplatinum. Now, the purpose of the treatment for osteosarcoma are assurance of their life and functional and beautiful limb-sparing. Recently, preoperative chemotherapy for limb saving is given to patients with osteosarcoma of the extremities. The five year survival rate increased to 65% and limb sparing rate became above 50%. It is generally accepted that pre- and 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.

[Cis-dichlorodiammineplatinum in osteosarcoma. Osteosarcoma Cooperative Study Group report].

Thirty-two patients with primary osteosarcoma and 18 patients with advanced osteosarcoma were treated by iv or ia infusion of cisplatinum at a dose of 100 mg/m2 every three weeks. The efficacy of the agent for primary osteosarcoma was mainly estimated by X-ray findings and histologic examination. One patient had a partial response, and 7 patients had a minor response. Pathologic evaluation of the extent of the primary tumor necrosis was performed on 27 resected specimens. Eight of 27 cases showed a good response (Ayala III A less than). One of 18 patients with advanced osteosarcoma had a partial response, and 2 a minor response. Nausea and vomiting (88%), liver dysfunction (42%), leukopenia (36%), nephrotoxicity (20%) and auditory disturbance (20%) were the main side effects in 50 patients. However, side effects of cisplatinum were generally reversible. The results suggest that cisplatinum is effective against osteosarcoma and may enhance the therapeutic results in osteosarcoma.

[Operative treatment of bone and soft tissue tumors involving pelvic region, especially retroperitoneal area including lumbar region].

During the past 17 years, 35 of 60 patients with malignant bone and soft tissue tumors of the pelvic and surrounding tissues, were treated surgically. There were 13 bone tumors and 22 soft tissue tumors, There were 12 recurrent cases and 23 non-recurrent cases with cumulative 5-year survival rates of 20% and 70%, respectively. In the tumors involved even in the iliolumbar area, curative resection was difficult with poor prognosis. Serious complications also developed with high incidence immediately after operation, including ileus, severe infections and postoperative bleeding. When the affected limb was preserved, many difficulties were encountered in functional recovery. Therefore, we combine preoperative radiation and intra arterial infusion for the prevention of recurrence at the resection margin. However, we have not obtained completely satisfying results. Operations involving these tumors should be performed in cooperation with other fields.

[Efficacy and problems of radio- and chemo-combination therapy for malignant bone tumors].

In this study we reviewed cases of osteosarcoma, malignant lymphoma of bone and Ewing's sarcoma. Historically, osteosarcoma was unresponsive to chemotherapy. Most patients were treated by radiation or amputation alone and 80% of them died from pulmonary metastasis within 2 years. Five-year survival rate was 13%. Introduction of ADM, HD-MTX and CDDP improved dramatically the prognosis of these cases. Five-year survival rate was 60%. On the other hand, 11 cases of malignant lymphoma of bone and 4 cases of Ewing's sarcoma were treated by radiation with no local recurrence. VEPA or CHOP chemotherapy was used for the former with a five-year survival rate of 45%. For the latter, T-11 protocol (Rosen) was applied, and all patients survive with no metastasis. Other organ injuries circulatory disturbance, bone necrosis and growth-disturbance of bone in radiotherapy, myocardiopathy caused by ADM and renal toxicity of CDDP are all problematic.

The alteration in the pattern of pulmonary metastasis with adjuvant chemotherapy in osteosarcoma.

Alterations in the pattern of pulmonary metastasis of patients with osteosarcoma treated with adjuvant chemotherapy were studied. Thirty two patients who were treated with both radical surgery and adjuvant chemotherapy were observed (chemotherapy group). As a control, sixty two patients treated with radical surgery alone were also assessed (non-chemotherapy group). The chemotherapy group demonstrated a reduction in the number and a delay in the appearance of metastases. The tumour doubling time did not differ between the chemotherapy and non-chemotherapy groups. The initial site of metastasis among the chemotherapy group was most commonly in the lower lung field, whereas among the non-chemotherapy group it was usually to the middle lung field. The chemotherapy group survived longer than the non-chemotherapy group after developing pulmonary metastases. Histological examination showed that the metastatic foci stimulated the primary sites.