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PubMedDate not supplied

Tumor angiogenesis and outcome in osteosarcoma.

Intratumoral angiogenesis quantified by microvessel density (MVD) has been shown to be a strong prognostic indicator in a number of malignant tumors. Its association with prognosis in bone sarcomas has been subject to less extensive research. The aim of this study was to investigate prognostic significance of angiogenesis in osteosarcoma. Thirty-nine patients with osteosarcoma were included in a retrospective immunohistochemical study. Sections from diagnostic biopsies were immunostained using anti-von Willebrand factor antibody and microvessels were counted at 400 x magnification on 3 microscopic fields per patient. MVD was correlated with overall and disease-free survival by Kaplan-Meier and log-rank analysis. Correlation between clinicopathological variables and the degree of angiogenesis was tested using a chi 2 test. Significant statistical difference was found regarding overall survival and disease-free survival between patients with high (> 32.3 vessels/field) and low (< or = 32.3 vessels/field) microvessel counts (log-rank test p = .0196 and p = .0147, respectively). The rate of metastasis was significantly higher in patients with high microvessel counts (p = .042). These findings strongly suggest that angiogenesis quantified by microvessel density is predictive of metastasis and poor prognosis in osteosarcoma.

Adolescent↗
PubMedDate not supplied

The stomach and pulmonary interlobular space as unusual sites of osteosarcoma.

The authors report a girl with high-grade intraosseous osteosarcoma of the left femur who lost one eye during early infancy for an unknown reason. Nine months after treatment, osteosarcoma in the stomach was detected and completely excised when the girl underwent endoscopy for Helicobacter pylori infection. Three years later osteosarcoma in the pulmonary interlobular space was noticed and completely removed. The girl is doing well and free of disease 26 months after the last resection.

Child↗
PubMed2004

Terminal osteoblast differentiation, mediated by runx2 and p27KIP1, is disrupted in osteosarcoma.

The molecular basis for the inverse relationship between differentiation and tumorigenesis is unknown. The function of runx2, a master regulator of osteoblast differentiation belonging to the runt family of tumor suppressor genes, is consistently disrupted in osteosarcoma cell lines. Ectopic expression of runx2 induces p27KIP1, thereby inhibiting the activity of S-phase cyclin complexes and leading to the dephosphorylation of the retinoblastoma tumor suppressor protein (pRb) and a G1 cell cycle arrest. Runx2 physically interacts with the hypophosphorylated form of pRb, a known coactivator of runx2, thereby completing a feed-forward loop in which progressive cell cycle exit promotes increased expression of the osteoblast phenotype. Loss of p27KIP1 perturbs transient and terminal cell cycle exit in osteoblasts. Consistent with the incompatibility of malignant transformation and permanent cell cycle exit, loss of p27KIP1 expression correlates with dedifferentiation in high-grade human osteosarcomas. Physiologic coupling of osteoblast differentiation to cell cycle withdrawal is mediated through runx2 and p27KIP1, and these processes are disrupted in osteosarcoma.

Animals↗
PubMed1999

Interferon-alpha enhances the sensitivity of human osteosarcoma cells to etoposide.

The purpose of these studies was to determine whether interferon-alpha (IFN-alpha) could enhance the sensitivity of human osteosarcoma cells to the cytotoxic actions of etoposide (VP-16). Cytostasis was determined using a [3H]thymidine incorporation assay, whereas cytotoxicity was quantified by a colony-formation assay. Low concentrations (0.1-5 U/ml) of IFN-alpha enhanced the cytostatic activity of VP-16 against MG-63, SAOS-2, and TE-85 osteosarcoma cells. The cytostatic activity of 1 microM VP-16 rose from 11% to 64%, 9% to 31%, and 10% to 71%, respectively, in the three cell lines when IFN-alpha was present. Survival fraction was also decreased when the osteosarcoma cells were treated with VP-16 + IFN-alpha as compared to either agent alone. The interaction between these two agents was determined to be synergistic rather than additive by interaction index analysis. Similar effects on cytostasis and cytotoxicity were observed when IFN-alpha was combined with Adriamycin but not cisplatin, actinomycin D, vinblastine, or amsacrine. VP-16 uptake was enhanced 12-fold in the presence of IFN-alpha, but this did not appear to translate into an increase in topoisomerase-II (topo-II)-DNA complex formation as quantified by the sodium dodecyl sulfate-KCl precipitation assay. We also could not detect alterations in topo-II expression, topo-II protein production, or cell cycle kinetics that have been shown to correlate with increased VP-16 cell sensitivity. Therefore, at this time the mechanism of enhanced cell sensitivity to the combination treatment remains unclear.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

In vitro and in vivo enhancement of canine pulmonary alveolar macrophage cytotoxic activity against canine osteosarcoma cells.

The combination of chemotherapy with immunotherapy may offer an advantage over either therapy alone and provide a greater potential for total tumor eradication. Monocyte/macrophage-mediated tumor cell killing is a major mechanism of the host's defense against primary and/or metastatic neoplasia. We evaluated the tumoricidal activity against canine osteosarcoma cells of canine pulmonary alveolar macrophages (PAM) exposed in vitro to two recombinant canine (rc) cytokines (rcTNF alpha and rcIFN gamma). We also evaluated the in vivo tumoricidal activity of PAM from dogs treated with the macrophage activator, liposome-encapsulated muramyl tripeptide-phosphatidyl-ethanolamine (L-MTP-PE) alone or in combination with doxorubicin (DOX). This study demonstrated that rcTNF alpha and rcIFN gamma significantly enhance in vitro canine PAM cytotoxicity against canine osteosarcoma cells, and that PAM from dogs treated with DOX + L-MTP-PE have enhanced cytotoxic activity against osteosarcoma cells when compared to dogs treated with DOX or L-MTP-PE alone. These findings support the rationale for combining a chemotherapy agent with an immunotherapy agent for the treatment of metastatic disease, and suggest a role for TNF alpha and IFN gamma as agents for stimulating the antitumor activity of macrophages.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1992

Primary chemotherapy and delayed surgery for osteosarcoma of the extremities with synchronous metastases.

From September 1986 to September 1989 11 patients affected by osteosarcoma of the extremities with synchronous metastases were treated with two cycles of high-dose methotrexate i.v., cisplatin i.a. and adriamycin i.v. followed by simultaneous resection of the primary and metastatic tumor. A complete histological examination of the resected specimens was always performed to evaluate the percentage of necrosis produced by chemotherapy on both the primary and metastatic tumor. After surgery the patients received 3 more cycles of the same drugs as used preoperatively plus ifosfamide. The histological response of the primary tumor was 'good' (90% or more tumor necrosis) in 4 patients and 'poor' (less than 90% of tumor necrosis) in 7, while in the 34 metastatic nodules the resulting necrosis was good in 8 and poor in 26. A good correlation between the histological response in the primary and metastatic tumor was observed, particularly for poor responders (91% of poor responses also in metastatic nodules). At an average follow-up of 42 months, only 3 patients are alive, 2 disease-free, and one with uncontrolled disease. These data suggest that the prognosis of osteosarcoma of the extremities with synchronous metastases remains poor, even with a very aggressive treatment. Our results also seem to confirm the validity of the present strategy in the treatment of non-metastatic osteosarcoma: introducing new drugs post-operatively in poor responding patients can allow a better treatment of microscopic disease and can improve the prognosis for these patients.

Adolescent↗
PubMed1992

The treatment of osteosarcoma: present trends. The Scandinavian Sarcoma Group experience.

The study comprised 97 patients treated by the Scandinavian Sarcoma Group for high-grade, extremity-localized osteosarcoma. Chemotherapy was according to the T-10 protocol, with four courses of high-dose methotrexate (HDMTX) given preoperatively at weekly intervals. Seventeen percent of the patients obtained a good (grade III or IV) histologic response, 62% a moderate (grade II) response and 21% a poor (grade I) response. Grade II-IV responders had significantly higher serum MTX levels than grade I responders. Good responders had significantly better survival than moderate/poor responders, and had a trend towards both lower recurrence rate and longer time to recurrence. Five-year overall and relapse-free survival for all patients was 63% and 53%, respectively. Within a group of patients with similar primary tumour response, there was a trend for better survival with increasing serum MTX levels, indicating that individualization of MTX doses according to renal excretion rates may be indicated. The present results underline the importance of introducing effective chemotherapy from the start of osteosarcoma treatment, and that HDMTX alone seems to be insufficient preoperative therapy. The toxicity of HDMTX is generally mild, but we have by cerebral MRI found signal changes in white matter in 14/22 patients; changes that may represent subclinical MTX CNS toxicity. In the subsequent SSG osteosarcoma protocol, cisplatin and doxorubicin has been added to HDMTX from the start of treatment. Our data also suggest that an aggressive approach involving second-line chemotherapy and surgery is indicated for metastatic disease and that such an approach may lead to long-term survival in up to 30% of patients.

Adolescent↗
PubMed2003

Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide.

BACKGROUND: Effective adjuvant or neoadjuvant regimens of chemotherapy have dramatically improved the prognosis of patients with high-grade osteosarcoma of the extremity, localized at diagnosis. Currently, little is known about patients with metastatic disease at presentation. PATIENTS AND METHODS: From May 1995 to May 2000, 57 patients with osteosarcoma of the extremity, metastatic at presentation, were treated according to the following scheme: primary chemotherapy, restaging, simultaneous resection of primary tumor and metastatic lesions, and maintenance chemotherapy. RESULTS: Thirty-five patients achieved remission. At a follow-up ranging from 2 to 7 years, seven remained continuously free of disease, one died of chemotherapy-related toxicity and 27 patients relapsed. Twenty-one of the 22 patients who never achieved remission died as a result of the tumor, as well as 20 of the 27 who achieved remission but then relapsed. Of the remaining seven relapsing patients, six are alive with uncontrolled disease, while one is alive and free of disease 24 months after the last post-relapse treatment. Two-year event-free survival (EFS) and overall survival (OS) were 21% and 55%, respectively. These results are significantly poorer than those achieved in 128 contemporary patients with non-metastatic disease at presentation, treated with the same chemotherapy protocol (2-year EFS and OS of 75% and 94%, respectively). CONCLUSIONS: The results of our study confirm that the prognosis of patients with osteosarcoma of the extremity, metastatic at presentation, remains poor, despite the use of aggressive treatments.

Adolescent↗
PubMed1988

Neoplastic transformation of osteogenic cells: quantitative morphometric analysis of an in vitro model for osteosarcoma.

Previously we have reported the development of a model in vitro system for the study of osteosarcoma. In this system, when chick periosteal explants are infected with Fujinami sarcoma virus (FSV), osteosarcoma-like tissue is formed. In the present study, a series of histopathologic parameters of neoplastic transformation and osteogenesis were quantitated, at a single cell level, by computer-assisted morphometry. Most significantly, it was found that compared to uninfected (control) cultures, in the FSV-infected (experimental) cultures, the bone to osteoid ratio per unit area was decreased due to a relative decrease in the area of bone and an increase in the area of osteoid. The cellularity of the FSV-infected tissues was significantly increased due to an increase in the number of unlabeled and [3H]thymidine-labeled cells, while the proportion of alkaline phosphatase (AP) positive cells decreased. Double-label immunohistochemistry (with anti-P140gag-fps) and histochemistry for AP activity was performed, to demonstrate production of the oncogene-encoded protein, and osteoblastic differentiation respectively. In an in vitro transformation assay, single cells derived from control, uninfected cultures did not grow, while those derived from FSV-infected cultures formed colonies in semisolid medium. Some of these colonies demonstrated AP staining. Taken together these data show that in this in vitro system (i) neoplastic transformation of osteogenic cells does occur, (ii) changes in osteoid and bone production are related to neoplastic transformation, and (iii) osteosarcoma-like changes can be quantitated at the individual cell level.

Animals↗
PubMed2001

Synchronous multifocal osteosarcoma with lymphatic spread in the lung: an autopsy case report.

Synchronous multifocal/multicentric osteosarcoma (MOS) is a rare variant of osteosarcoma. We report here an autopsy case of a 15-year-old boy with MOS. Radiological examinations showed multiple sclerotic lesions in the left distal femur and in the ipsilateral proximal tibia without pulmonary metastasis at the first examination. Histological examination showed osteoblastic-type osteosarcoma. Despite high-dose chemotherapy the patient died of multiple bone and lung involvements 6 months after the initial diagnosis. Autopsy examination revealed prominent invasion of the tumor cells into lymphatic vessels and pleural dissemination without the formation of bulky, nodular metastasis in the lungs. Metastases in pulmonary hilar lymph nodes were noted without metastasis in other organs. Immunohistochemistry revealed that p53 protein was positive in most of the tumor cells. In summary, the present case was characterized by multiple bone involvement and prominent lymphatic spread of sarcoma cells in the lungs.

Adolescent↗
PubMed1976

Monitoring of murine osteosarcoma by serial alkaline phosphatase determinations.

To establish that alkaline phosphatase (AP) was released by osteosarcoma cells, we measured this enzyme in C3H/HeJ mice with im-implanted osteosarcoma and in in vitro cultures of neoplastic cells subjected to short-term incubation. We found that 10(5) osteosarcoma cells synthesized a significant amount of AP in vitro in 30 minutes at 37 degrees C. A good correlation existed between pulmonary metastatic tumors and the AP values. Serum AP measurements indicated approximate sizes of disseminated and localized tumors, but could not monitor early localized tumors.

Alkaline Phosphatase↗
PubMed1997

P-glycoprotein expression: critical determinant in the response to osteosarcoma chemotherapy.

BACKGROUND: Fewer than 20% of patients with bone cancer who are treated with surgery alone are cured. Even with the best current treatment, surgery combined with chemotherapy, only 60%-80% of patients with nonmetastatic bone cancer and 10% of patients with metastatic bone cancer are cured. Thus far, the reason for treatment failure in the nonresponding subset has not been identified. It has been hypothesized that P-glycoprotein, which confers multidrug resistance, might be the cause. We sought to determine whether the expression of P-glycoprotein is associated with poor treatment outcome in osteosarcoma. METHODS: In a retrospective study, we correlated P-glycoprotein expression with the outcome of conventional chemotherapy in 62 consecutive, clinically staged patients diagnosed as having osteosarcoma between 1980 and 1989. RESULTS: P-glycoprotein was overexpressed in 27 patients but not in another 34 patients, and expression was ambiguous in the sample from one patient. At a median follow-up of 8.9 years, the 34 patients whose tumors did not express P-glycoprotein had significantly better relapse-free rates than the 27 subjects whose tumors expressed the protein (87% versus 0%; P<.00001) and had improved survival rates (94% versus 35%; P<.00001). Among the 46 patients who received chemotherapy before surgery, the 23 whose tumors were negative for P-glycoprotein showed significantly better long-term outcomes (P<.00002), although differences in tumor necrosis in response to therapy were only of borderline significance (P = .057). CONCLUSIONS: P-glycoprotein expression does correlate with treatment failure in patients with osteosarcoma. This correlation raises the possibility that inhibiting the action of P-glycoprotein as part of therapy for this disease would improve outcome.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Synchronous multifocal osteosarcoma: results in twelve patients treated with neoadjuvant chemotherapy and simultaneous resection of all involved bones.

BACKGROUND: Multifocal osteosarcoma is a rare type of tumor which is always excluded from therapy trials and is therefore rarely investigated for prognosis and treatment. PATIENTS AND METHODS: Twelve patients with synchronous multifocal osteosarcoma underwent neoadjuvant chemotherapy and, when feasible, simultaneous resection of involved bones. RESULTS: Four patients were unsuitable for resection and died 5-13 months (average 9 months) later. In eight patients all lesions were resected simultaneously. Four patients are disease-free at 15, 20, 24, and 60 months (average 29 months), and four relapsed and died at 12, 24, 30 and 36 months (average 30.5 months). CONCLUSIONS: Chemotherapy associated with aggressive surgery may be useful. The histological response of different lesions in the same patient are strongly correlated, confirming that synchronous multifocal osteosarcoma is not originally multicentric but unicentric with bone metastases.

Adolescent↗
PubMed1991

Zürich experience with preoperative, high dose methotrexate-containing chemotherapy in patients with extremity osteosarcomas (OSA).

From 1979 to 1990, 37 patients with extremity osteosarcomas, 22 of them males and 15 females, median age 19 years, received pre- and postoperative chemotherapy. The period of observation, calculated from after the primary operation, ranged from 1-114 months, median 25 months. After preoperative chemotherapy, 9 (24%) underwent a primary amputation, in 28 (76%) a limb salvage procedure was possible, 4/29 (14%) later developed local recurrences, metastases were diagnosed in 8/9 amputees and 5/28 after limb-sparing surgery. The five-year disease-free and overall survivals after amputation are 11% and 33%, respectively, compared to 68% and 75%, respectively (p = 0.001 and 0.018, respectively, for long rank). Results of histologic assessment after preoperative chemotherapy are of significant prognostic impact. The earlier prognostic groups of 0%-49% necrosis versus 50%-100% necrosis were statistically no longer suitable for distinguishing useful prognostic groups. In this second analysis, patients with 0%-79% necrosis versus 80%-100% necrosis had 5-year disease-free survivals of 81% versus 44% (p = 0.032) and 5-year overall survivals of 88% In summary, 24% of our patients with extremity osteosarcomas, most of them with large primaries close to joints, had to undergo primary amputation and had only a 33% 5-yr-survival, whereas limb salvage procedures with pre-and postoperative chemotherapy were associated with a 5-yr survival of 75% and thus had no adverse impact. Careful selection of patients for successful management of osteosarcomas is important; necrosis of 80% and more after preoperative chemotherapy is a prerequisite for a favourable outcome.

Adolescent↗
PubMed1984

FBJ virus-induced osteosarcoma contains type I, type I trimer, type III as well as type V collagens.

The FBJ osteosarcoma (a virus-induced osteosarcoma named after its discoverers, Finkel, Biskis, and Jinkins) contains an extensive extracellular matrix. Collagens were extracted by digestion with pepsin in dilute acetic acid from tumors grown in lathyritic mice and fractionated by differential salt precipitation, yielding five fractions. Fraction 1 (precipitated at acidic 0.7 M and neutral 2.0 M NaCl) gave rise mainly to alpha 1(III) chain on phosphocellulose column chromatography. The alpha 1(III) chain was identified by its typical behavior on interrupted electrophoresis and analysis of the CNBr-cleaved peptides. The alpha 1(III) chain of the FBJ tumor had a high content of hydroxylysine and neutral saccharide. Fraction 2 (precipitated at acidic 0.7 M and neutral 4.5 M NaCl) yielded alpha 1(I) and alpha 2(I) chains on the phosphocellulose column from which alpha 1(I) was eluted as a broad peak, conceivably reflecting a high content of hydroxylysine and neutral saccharide. Fraction 4 (precipitated at acidic 1.2 M and neutral 4.5 M NaCl) yielded type V collagen, which also featured an exceptionally high content of neutral saccharide (Yamagata, S., et al. (1982) Biochem. Biophys. Res. Commun. 105, 1208-1214). The proportions of type I, type I trimer, type III, and type V collagens extracted by pepsin digestion from FBJ tumor were calculated to be 33, 29, 26, and 12%, respectively. The FBJ tumor is free from invasion by blood vessels, shows no deposition of calcium, and thus has the appearance of cartilage. But type II collagen, a specific gene product of cartilage, could not be identified in any of the fractions analyzed. Contrary to its appearance, collagen type analyses indicate that FBJ osteosarcoma is literally induced from osteogenic cells.

Amino Acids↗
PubMed1996

Cutaneous metastasis of an osteosarcoma. A case report.

Sarcomas seldom metastasize to the skin. This report describes a rare instance of this phenomenon. A 24-year-old patient with a history of osteosarcoma (osteoblastic type) of the right humerus was seen with a cutaneous nodule on the left temple. Histologic examination of the skin showed the lesion to be a metastatic osteosarcoma. On histologic examination, a proliferation of bizarre mononucleated or multinucleated osteoblastic cells was noted in the dermis and subcutis. Although osteoid formation and calcification were not recognized, as they had been in contrast to the primary lesion, basic structures and components of the skin lesion were identical to those of the primary tumor tissue. Cutaneous metastasis from on osteosarcoma of bone is an extraordinarily rare event and, as far as we can determine, has only been reported three times.

Adult↗
PubMed2000

Primary osteosarcoma of metatarsal bone.

Primary osteosarcomas of the short tubular bones of hands and feet are rare. We describe a 46-year-old woman with osteosarcoma of the left metatarsal bone with pulmonary metastases. This is the first reported case of osteosarcoma at this site.

Biopsy↗
PubMed2002

Dose-intense ifosfamide/doxorubicin/cisplatin based chemotherapy for osteosarcoma in adults.

The efficacy of neoadjuvant and adjuvant chemotherapy has been clearly established in the treatment of osteosarcoma; however, the most active regimen remains to be identified. This prospective study evaluated the efficacy and toxicity of a dose-intense ifosfamide, doxorubicin, and cisplatin-based neoadjuvant regimen in adults with osteosarcoma. We prospectively treated 20 patients with osteogenic sarcoma with two cycles of ifosfamide/doxorubicin followed by two cycles of doxorubicin/cisplatin every 2 weeks. Surgical specimens were analyzed for percent tumor necrosis. Patients who demonstrated a "good response" (GR) to chemotherapy received the same combination postoperatively at a lower dose rate. Patients who demonstrated a "poor response" (PR) received four cycles of high-dose methotrexate alternating with two cycles of ifosfamide/etoposide and two cycles of cisplatin/etoposide after the surgery. Neoadjuvant chemotherapy was well tolerated with moderate hematologic toxicity. Twelve of 19 evaluable patients (63%) were treated according to the GR arm and 7 according to the PR arm. At median follow-up of 5.5 years, disease-free survival (DFS) and overall survival (OS) are 68% and 74%, respectively. Patients treated on the GR arm had DFS and OS of 75% and 83%, respectively, whereas patients on the PR arm had DFS and OS of 57%. Intensive neoadjuvant chemotherapy is effective and moderately well tolerated in patients with de novo osteosarcoma. The outcome data suggest that lack of a near complete response to preoperative chemotherapy reflects inherent biologic resistance to chemotherapy and hence a poor prognosis.

Adult↗