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PubMed2000

Clinical significance of tenascin-C expression in osteosarcoma: tenascin-C promotes distant metastases of osteosarcoma.

Tenascin-C (TN-C) is one of extracellular matrix glycoproteins. We have immunohistochemically examined the TN-C expression of 33 primary osteosarcoma paraffin-embedded samples. The TN-C expression of the patient group with metastases was higher than that of the group without metastases at significant difference, and the survival curves show a tendency for poor outcome in the high grade staining group. Moreover, the supplemental TN-C had an effect of easier migration of a human osteosarcoma cell line (HOS) in vitro. The results may suggest that TN-C help osteosarcoma cells to migrate and to metastasize.

Adolescent↗
PubMedDate not supplied

Immunoscintigraphic detection of primary and metastatic spontaneous canine osteosarcoma with F(ab')2 fragments of osteosarcoma-associated monoclonal antibody TP-1.

Monoclonal antibody TP-1 has been shown to bind selectively to human and canine osteosarcoma cells in vitro using immunohistochemical stains. This report describes the in vivo administration of radioiodinated F(ab')2 fragments of monoclonal antibody TP-1 in dogs with primary and/or metastatic spontaneous osteosarcoma. Two dogs were injected with 131labeled F(ab')2 TP-1 and two dogs were injected with 123labeled antibody fragments. Immunoscintigraphy successfully demonstrated the radiolabeled antibody fragments in 6/6 known primary or metastatic lesions and in addition detected 4 metastatic lesions not diagnosed by conventional radiographs. Concurrent imaging of 99mTc labeled autologous erythrocytes in two dogs confirmed that the accumulation of radiolabeled antibody fragments was independent of the blood pool. There was no immunoscintigraphic evidence of localization of radioiodine to normal organs or tissues other than those expected to accumulate free iodine. The present study has demonstrated the potential of monoclonal antibody TP-1 F(ab')2 fragments for early detection of metastatic spread of spontaneous osteosarcoma.

Animals↗
PubMed1992

Analysis of a metastasizing testicular mixed gonadal stromal tumor with osteosarcoma components suggests that a malignant tumor with the histology of osteosarcoma may develop without primary involvement of RB1 and TP53.

A malignant stromal tumor of the testis with an osteosarcoma component and five of its metastases mainly containing osteosarcoma have been analyzed for RB1 and TP53 abnormalities. Whereas in the primary tumor and in some of the metastases loss of heterozygosity could not be detected for RB1 or for the 17p13 region in which TP53 is located, other metastases showed such losses of heterozygosity. By polymerase chain reaction analysis an 18-base pair deletion from exon 5 of the TP53 gene was found in a small proportion of primary tumor cells and in one of the metastases, but not in the other metastases. Therefore, in this case neither RB1 nor TP53 seems to play an essential role in the initiation of osteosarcoma.

Amino Acid Sequence↗
PubMed2006

Highly frequent allelic loss of chromosome 6q16-23 in osteosarcoma: involvement of cyclin C in osteosarcoma.

The molecular pathogenesis of osteosarcoma is very complicated and associated with chaotic abnormalities on many chromosomal arms. We analyzed 12 cases of osteosarcomas with comparative genomic hybridization (CGH) to identify chromosomal imbalances, and detected highly frequent chromosomal alterations in chromosome 6q, 8p, 10p and 10q. To define the narrow rearranged region on chromosome 6 with higher resolution, loss of heterozygosity (LOH) analysis was performed with 21 microsatellite markers. Out of 31 cases, 23 cases (74%) showed allelic loss at least with one marker on chromosome 6q. We identified two distinct commonly deleted regions on chromosome 6 using markers D6S1565 located at 6q16 and 6q23MS1 at 6q23. The expression analysis of genes located at the deleted region was performed, and the decreased mRNA expression of the CCNC gene, one of the regulators of cell cycle, was detected. Growth of osteosarcoma cell line was significantly suppressed after the CCNC cDNA transfection. Fine mapping of the deleted region containing a possible tumor suppressor gene and the transfection assay suggest that the CCNC is a candidate tumor suppressor gene.

Cell Line, Tumor↗
PubMed1991

Adjuvant chemotherapy of high-grade osteosarcoma of the extremity. Updated results of the Multi-Institutional Osteosarcoma Study.

The Multi-Institutional Osteosarcoma Study (MIOS) was designed to determine whether intensive multiagent adjuvant chemotherapy improves the outcome of patients with nonmetastatic high-grade osteosarcoma of the extremity as compared with concurrent controls. After definitive surgery of the primary tumor, patients were randomly assigned to immediate adjuvant chemotherapy or to observation without adjuvant treatment. Updated results of this trial indicate that the projected six-year event-free survival for the control group is 11% compared to 61% for the chemotherapy group (p less than 0.001). Similar results were observed in patients who declined randomization but who were followed according to the treatment arms of the protocol. When randomized and nonrandomized patients are pooled according to assigned treatment, a survival advantage favoring those patients treated with immediate adjuvant chemotherapy is apparent. An analysis of prognostic factors among patients receiving immediate adjuvant chemotherapy reveals that elevation of the serum lactic dehydrogenase at diagnosis is the factor most predictive of adverse outcome. Location of the primary site in the tibia confers a favorable prognosis. The authors conclude that the natural history of high-grade osteosarcoma of the extremity has not changed over the past two decades. The administration of immediate adjuvant chemotherapy has a significant favorable impact on event-free survival and should be recommended for all such patients.

Adult↗
PubMed1988

[Scintigraphic follow-up of osteosarcoma during neoadjuvant chemotherapy. Results of the cooperative osteosarcoma study of the Society for Pediatric Oncology].

The response of osteosarcomas to preoperative chemotherapy as measured by quantitative 99mTc-diphosphonate scintigraphy was compared with the amount of tumor cell destruction found histologically in the resected specimens. 3-phase bone scintigraphy, with determination of tumor/non-tumor (T/NT) ratios, allowed accurate prediction of tumor response in 28 of 30 tumors (accuracy = 93%) after completion and in 10 of 12 osteosarcomas (83%) at the half-way stage of preoperative chemotherapy, when only those tumors were evaluated which showed convergent changes of T/NT ratios in the perfusion and the mineral phase. At the half-way stage, however, evaluation of chemotherapy effects was complicated in 12 of 23 osteosarcomas by diverging T/NT ratios. In contrast, quantification and mapping of the tumor plasma volume and 99mTc-diphosphonate clearance on parametric images predicted correctly the histological tumor response to chemotherapy in 10 of 11 tumors (91%) after completion and in all 11 cases (100%) at the half-way stage.

Adolescent↗
PubMed1989

[Transplantable osteosarcomas in rats. I. The growth behavior of spontaneous and 4-HAQO induced osteosarcomas in rats].

While there are a number of experimental animal models for osteosarcoma development, the available rat systems are limited both in number and applicability. The present report concerns our attempts to establish an appropriate rat model to allow development of new experimental approaches to human osteosarcoma. A spontaneously occurring osteosarcoma (J. H. 1-OS) was found in a 35 week old male rat. The tumor could be transplanted and grew well and although the bone forming activity decreased after the 18th generation, the growth potential remained high.

4-Hydroxyaminoquinoline-1-oxide↗
PubMedDate not supplied

Immunohistochemical detection of osteosarcoma-associated antigen in canine osteosarcoma.

Monoclonal antibodies TP-1 and TP-3, which detect an antigen expressed on the cells of human osteosarcoma, were tested by immunohistochemical staining for binding to normal and neoplastic canine tissues. In dogs, as in man, TP antibodies stained the tumor cells of all (13/13) osteosarcomas tested. Limited staining was found in a wide range of normal canine tissues. A proportion of cells in some canine carcinomas also stained, which was unexpected on the basis of the unique mesenchymal specificity of these antibodies in human tissues. TP monoclonal antibodies detect epitopes common to osteosarcomas in man and dog and are potentially valuable for the in vitro and in vivo comparative study of this tumor.

Animals↗
PubMedDate not supplied

[Neoadjuvant chemotherapy of osteosarcoma. Preliminary results of the cooperative COSS-86 osteosarcoma study].

The neoadjuvant study COSS-86 was undertaken aiming at (1) improving the cure rate in osteosarcoma by early intensification of chemotherapy in high risk patients and (2) investigating the effect of intraarterial (i.a.) versus intravenous (i.v.) administration of cisplatinum. (1) Ifosfamide was added to the well proven drugs in osteosarcoma such as doxorubicin, high-dose methotrexate and cisplatinum in patients with large tumor size or/and high portion of chondroid groundsubstance or/and scintigraphic nonresponse after 4 weeks of preoperative chemotherapy. It was given in combination with cisplatinum. (2) The same patients were allocated to either the intraarterial study arm or the intravenous control arm of the study. The response rate (greater than 90% tumor necrosis) of all patients was 75% (88/118). No advantage in response rate was achieved by i.a. infusion of cis-platinum within this highly efficient 4-drug regimen (i.a. 75% (33/44) vs. i.v. 74% (35/47)). The significantly improved response rate in this study results in a better metastasis free survival (MFS) of 77% (+/- 4) at 4 years.

Adolescent↗
PubMedDate not supplied

Ultrastructure of low-grade intraosseous osteosarcoma of bone: a comparative study with fibrous dysplasia and parosteal osteosarcoma.

The ultrastructure of low-grade intraosseous osteosarcoma (LGOS) is not well documented in the literature. Four cases of LGOS are described with an emphasis on its distinguishing characteristics as well those it shares with other lesions. The predominant cells of LGOS are fibroblasts with well-developed rough endoplasmic reticulum and mild focal immunoreactivity to SMA and MSA. Few osteoblasts and myofibroblasts are present. Transition cells between fibroblasts and osteoblasts are also noted. The fibroblasts are closely related to osteoblasts from a histological and functional point of view, and phenotypically are probably modified osteoblasts. Comparative ultrastructural studies between LGOS and fibrous dysplasia (FD) reveal basic similarities, although the cells in LGOS are larger with more of an abundance of organelles. Therefore, accurate differentiation between these two lesions rests at the histological and radiological levels. LGOS and parosteal osteosarcomas (PO) also share similar ultrastructural features. In the case samples in this study, an unusual type of multilayered amorphous material was found in the osteoid matrix of a case of LGOS and one of PO. This probably emphasizes the morphologic similarities between these 2 tumors.

Adult↗
PubMed1991

Changing pattern of pulmonary metastases with adjuvant chemotherapy in patients with osteosarcoma: results from the multiinstitutional osteosarcoma study.

The multiinstitutional osteosarcoma study (MIOS), a randomized trial of adjuvant therapy for osteosarcoma with a concurrent control group, registered 113 patients from June 1982 to August 1984. Preliminary analysis of the study indicated a significant event-free survival advantage favoring immediate adjuvant chemotherapy, (P less than .001). For patients treated with surgery alone or with surgery and adjuvant chemotherapy, the lungs were involved in more than 80% of the relapses. Patients relapsing after surgery alone tended to relapse earlier (P less than .01), had more pulmonary nodules (P less than .01), and had more frequent bilateral pulmonary involvement (P less than .01) than those treated with immediate postsurgical adjuvant chemotherapy. However, patients relapsing after treatment with surgery alone experienced a significantly longer interval to further disease progression (P less than .01) and improved survival after relapse (P = .01) when compared with patients who relapsed after treatment with immediate adjuvant chemotherapy. The only factor predictive of survival after relapse was if the patient could be made surgically disease-free after initial relapse (P = .03).

Antineoplastic Agents↗
PubMed1994

Doxorubicin and cisplatin with granulocyte colony-stimulating factor as adjuvant chemotherapy for osteosarcoma: phase II trial of the European Osteosarcoma Intergroup.

PURPOSE: This report describes the toxicity and feasibility of administering doxorubicin (DOX) and cisplatin (CDDP) at 2-week intervals with granulocyte colony-stimulating factor (G-CSF) to patients with osteosarcoma and the compatibility of this regimen with endoprosthetic surgery performed after three cycles. PATIENTS AND METHODS: Twenty-four patients with biopsy-proven osteosarcoma were treated with three preoperative cycles of DOX 25 mg/m2/d on days 1 to 3 and CDDP 100 mg/m2 on day 1 with G-CSF 5 micrograms/kg/d on days 4 to 14. Surgery was scheduled at week 6 to be followed by three further cycles of chemotherapy at 2-week intervals. RESULTS: Two-week chemotherapy was feasible, but delays and dose reductions only allowed 74% and 78% of the intended dose-intensity of DOX and CDDP to be administered. Thrombocytopenia accounted for 50% of delays. Significant toxicity included neutropenic sepsis, severe mucositis, prolonged nausea and vomiting, and electrolyte disturbances. Twenty-one limb-salvage procedures and one amputation were performed. There were eight episodes of excessive perioperative bleeding. CONCLUSION: Intensive 2-week chemotherapy with intercurrent surgery is feasible and allows a greater dose-intensity of chemotherapy to be administered compared with the same regimen administered at 3-week intervals without G-CSF. The toxicity is considerable, but manageable.

Adolescent↗
PubMed1996

Experimental models for the study of drug resistance in osteosarcoma: P-glycoprotein-positive, murine osteosarcoma cell lines.

P-glycoprotein is an adenosine triphosphate-dependent drug-efflux pump that extrudes drugs from cells and causes drug-resistance. P-glycoprotein is believed to mediate drug-resistance in a wide variety of tumors. In this study, we developed two P-glycoprotein-positive, murine osteosarcoma cell lines that were resistant to Adriamycin (doxorubicin) (MOS/ADR1 and MOS/ADR2). We created the cell lines by short-term pulse exposures of the parent cell line to Adriamycin followed by single-cell cloning. The MOS/ADR1 and MOS/ADR2 cells were sevenfold and eighteenfold more resistant to Adriamycin than the cells from the parent line. Expression of P-glycoprotein, as examined with an immunofluorescence method, was detected in most of the MOS/ADR1 and MOS/ADR2 cells but not in the parent cells. After the cells had been incubated with Adriamycin for one hour, there was less accumulation of the drug in the resistant cell lines than in the parent cell line. The reduced accumulation was due to the increased efflux of Adriamycin. The Adriamycin-resistant cell lines demonstrated greater alkaline phosphatase activity than the parent cell line and produced more differentiated osteoblastic sarcomas in mice. Dose survival studies with use of a tetrazolium colorimetric assay showed that the MOS/ADR1 cells were cross-resistant to vincristine, vinblastine, etoposide, bleomycin, mitomycin C, and actinomycin D but not to dacarbazine, cisplatin, carboplatin, cytosine arabinoside, carmustine, cyclophosphamide, ifosfamide, methotrexate, and 5-fluorouracil. Although the MOS/ADR2 cells exhibited a similar spectrum of cross-resistance, they were more resistant than the MOS/ADR1 cells. We also tested the effect of three different resistance-modifying agents on the reversal of resistance to Adriamycin. We found that verapamil and trifluoperazine substantially reversed resistance to Adriamycin in the P-glycoprotein positive cell lines, whereas cyclosporin A was relatively ineffective. Because these cell lines retain the histological and biochemical features of bone-producing sarcomas and display the multidrug-resistant phenotype, they may be useful models for additional investigations of drug resistance in osteosarcoma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Primary cardiac osteosarcoma: multidisciplinary aspects applicable to extraskeletal osteosarcoma generally.

An osteosarcoma, primary in the right ventricular epicardium, produced pericardial constriction. Intense activity on technetium-99m bone scintigraphy led to a correct preoperative diagnosis. Biopsy of unrepresentative tissue clouded the diagnosis, and autopsy resolved the issue. Several clinicopathologic correlations are presented. Major therapeutic advances mandate early recognition of extraskeletal osteosarcoma, and the topic is reviewed in regard to cardiac cancers in general. The need to biopsy both hard and fleshy areas of unusual tumors is reviewed.

Aged↗
PubMed1976

A virally induced osteosarcoma in rats. A model for immunological studies of human osteosarcoma.

Inoculation of Moloney sarcoma virus into the medullary canal of the tibia in newborn Wistar-Lewis rats resulted in an initially localized osteosarcoma which usually metastasized to the lung and resulted in the death of the animal within four to five weeks. Tumor cells were grown in tissue culture and used as target cells in the assay of lymphocyte-mediated cytotoxicity using a microcytotoxicity and a radioisotope labeling method. Lymphocyte-mediated cytotoxicity was demonstrated throughout the course of the clinical disease as well as in a small number of animals which showed spontaneous regression of their tumors. Serum factors which could "block" or augment the cellular response were also identified. This model resembles the spontaneous osteosarcoma of humans in many respects and may be useful for studies of the human disease.

Animals↗
PubMed2007

Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup.

BACKGROUND: Previous randomized controlled trials that used the two-drug chemotherapy regimen of cisplatin and doxorubicin as the conventional arm showed no evidence of benefit from an increase in the number of agents or the length of treatment. It was then proposed that survival could be improved by increasing the planned dose intensity of cisplatin and doxorubicin. METHODS: Previously untreated patients with nonmetastatic, high-grade, central osteosarcoma of an extremity were randomly assigned to Regimen-C (conventional treatment with six 3-week cycles of cisplatin [100 mg/m2 by 24-hour infusion] and doxorubicin [25 mg/m2/day by 4-hour infusion for 3 days]) or to Regimen-DI (intensified treatment with identical total doses of cisplatin and doxorubicin, planned as six 2-week cycles supported by granulocyte colony stimulating factor (G-CSF). Surgery was scheduled for week 6 in both arms. Primary and secondary outcome measures were overall and progression-free survival, respectively. Intention-to-treat analyses were performed using standard survival analysis methods. Landmark analyses were performed in patients with known surgical details and centrally reviewed histologic response. All statistical tests were two-sided. RESULTS: Between May 1993 and September 2002, treatment was randomly allocated to 497 eligible patients. Six cycles of chemotherapy were completed by 78% of patients in Regimen-C and 80% of patients in Regimen-DI. The delivered preoperative median dose intensity of cisplatin was 86% in Regimen-C and 111% in Regimen-DI (as the percentage of that planned for the conventional regimen). Postoperative median dose intensity of cisplatin was 82% in Regimen-C and 110% in Regimen-DI (the corresponding figures for doxorubicin dose intensity were similar). Regimen-DI was associated with lower risks of severe leucopenia and neutropenia and higher risks of thrombocytopenia and mucositis. Good histologic response (>90% tumor necrosis) was observed in 36% of Regimen-C patients and 50% of Regimen-DI patients (P = .003, chi2 test). There was no evidence of a difference in overall survival (hazard ratio [HR] = 0.94, 95% CI = 0.71 to 1.24; P = .64) or progression-free survival (HR = 0.98, 95% CI = 0.77 to 1.24; P = .83). Landmark analyses showed similar results. CONCLUSIONS: Planned intensification of chemotherapy with cisplatin and doxorubicin increased received dose intensity and resulted in a statistically significant increase in favorable histologic response rate, but not in increased progression-free or overall survival. Our results call into question the use of histologic response as a surrogate outcome measure in trials of this disease.

Adolescent↗
PubMed2005

Aerosol gemcitabine inhibits the growth of primary osteosarcoma and osteosarcoma lung metastases.

Osteosacarcoma (OS) lung metastases are often resistant to chemotherapy. Most anticancer drugs are administered systemically. In many cases this is followed by dose-dependent toxicity, which may not allow the achievement of therapeutic levels in lungs to eradicate metastases. We determined the efficacy of gemcitabine (GCB) by administering it directly to the lungs via aerosol and studied the role of the Fas pathway in response to the therapy. We used 2 osteosarcoma lung metastases animal models: human LM7 cells that form lung metastases in mice following intravenous injection and murine LM8 cells, which grows subcutaneously in mice and spontaneously metastasize to the lung. Treatment was initiated when the presence of lung metastases had been established. Aerosol GCB inhibited the growth of lung metastases in mice. Intraperitoneal GCB administration at similar dosage had no effect on lung metastases. Besides its direct effect on lung metastases, aerosol GCB suppressed the growth of subcutaneous LM8 tumor. Histopathological examination of mice receiving aerosol GCB showed no evidence of toxicity. Lungs are distinguished from other tissues by the constitutive expression of FasL. Since exposure of tumor cells to GCB upregulated Fas expression, we hypothesized that the susceptibility of the tumor cells to ligand-induced cell death by resident lung cells may be increased. Therefore, the Fas pathway may contribute to the therapeutic effect of aerosol GCB.

Aerosols↗
PubMed1993

Treatment of osteosarcoma: experience of the Cooperative Osteosarcoma Study Group (COSS).

Using high-dose methotrexate, doxorubicin, and cisplatinum (or BCD) for adjuvant chemotherapy in osteosarcoma of the extremities, we achieved 8-year metastasis-free survival rates of 60-70%. No relapse has been observed after that time. A dose of 12 g/m2 of high-dose methotrexate seems superior to 6 g; doxorubicin was found to be indispensable for efficient therapy and administering ifosfamide in addition seemed to be beneficial. Primary chemotherapy appeared to be safe and to facilitate surgery. The response on chemotherapy provided valuable prognostic information. Salvage of poor responders by alternative postsurgical chemotherapy was unsuccessful. Intraarterial, as opposed to intravenous, use of cisplatinum, in addition to systemic three-drug chemotherapy, did not improve the local tumor response rate. The local failure rate was low (4.7%); it was higher, however, after limb-salvage procedures than after amputation and rotationplasty (11.1% vs. 2.2%, p < 0.05). The outcome after local failure was almost universally fatal. The most intriguing late sequelae of chemotherapy were cardiomyopathy due to doxorubicin and hearing loss due to cisplatinum. Given the limited number of effective drugs, it might be difficult to further improve the cure rate and also to diminish late toxicity. Exploration of the most effective but least toxic mode of drug administration might be one possibility. Another might be reduction of the cumulative doses and therapy duration, while simultaneously increasing the dose rate.

Antineoplastic Combined Chemotherapy Protocols↗