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PubMed1998

[The analysis of failures in therapy of osteosarcoma in children treated according to SFOP-94 protocol in the studies of Polish pediatric solid tumors treatment group].

Between December 1989 and April 1998 twenty eight children aged from 5 to 20 years (18 female and 10 male) suffering from osteosarcoma were treated according to the OS-SFOP-94 protocol. Twenty four patients presented with localized tumor of extremities and four with pulmonary metastases. The majority of primary tumors exceeded 150 ml of volume. The primary preoperative chemotherapy consisted of adriamycin (70 mg/m2 every four weeks) and high-dose methotrexate (12 g/m2 every week). In 20 patients limb-salvage surgery was applied, in three children--amputation and in one child tibia resection with genu arthrodesis was applied. Five of 28 patients died, one because of treatment related infection, 2 non-responders with metastatic osteosarcoma due to progressive disease, and one because of local relapse with pulmonary metastasis non-responding to therapy, one because of treatment refusal. Twenty one from 25 children are alive from 5 to 51 months. Event frae survival of children with localized disease calculated according to Kaplan-Meier analysis was 64.17% in the 51st month. The main cause of failure in the treatment of osteosarcoma in children is primary and secondary progression of disease. The toleration and results of treatment for osteosarcoma in children according to the OS-SFOP-94 is satisfactory.

Adolescent↗
PubMedDate not supplied

Sensitization and caffeine potentiation of cisplatin cytotoxicity resulting from introduction of wild-type p53 gene in human osteosarcoma.

The present study was performed to investigate whether the introduction of a wild-type p53 gene into human osteosarcoma cells could alter the growth rate and enhance the cytocidal effect of cisplatin (CDDP) and the synergistic antitumor effect of caffeine. The lipofection method was used to transfect a wild-type p53 expression plasmid into the human osteosarcoma cell line, Saos2, which has both p53 alleles deleted. The transfected cells, Saos2/p53, had a reduced growth rate compared with the parental cell line. The colorimetric WST-1 assay demonstrated that Saos2/p53 cells were twice as sensitive to CDDP alone at a 50% inhibition concentration than the parental Saos2 cells. Caffeine significantly potentiated the cytocidal effect of CDDP in the Saos2/p53 cells. Furthermore, the TUNEL assay revealed that following treatment both with CDDP alone and with CDDP combined with caffeine, a higher percentage of the Saos2/p53 cells underwent apoptosis than did the parental Saos2 cells. Therefore the cytocidal effect of CDDP and the synergistic antitumor effect of caffeine are enhanced by the introduction of a wild-type p53 gene into a human osteosarcoma cell line null for p53. This raises the possibility that gene therapy using the p53 gene may prove efficatious for human osteosarcomas lacking p53 and which are resistant to standard chemotherapy.

Apoptosis↗
PubMedDate not supplied

Metastasis of osteosarcoma to the maxilla--a case report.

Secondary osteosarcomas of the maxilla/premaxilla are extremely rare. We describe a case of a 24-year-old man with a metastasis of osteosarcoma to the premaxilla. The patient had undergone hip disarticulation followed by adria based chemotherapy for chondroblastic osteosarcoma of the proximal right femur ten years ago. The metastatic work up did not show liver or lung metastasis. The patient underwent premaxillectomy in February 1999. The histopathology revealed a chondroblatic osteosarcoma consistent with metastasis in the clinical setting. The patient was disease free at the end of five months.

Adult↗
PubMedDate not supplied

Fluorovisualization effect of acridine orange on mouse osteosarcoma.

If the localization of musculoskeletal sarcomas could be visualized during surgery, it would be possible to completely resect the tumor with minimum damage to normal tissues and the patients could retain a functional limb. Therefore, we conducted the present study to clarify the usefulness of acridine orange (AO) for fluorovisualization of tumors using a mouse osteosarcoma model. At 2 hours after injection of 10 mg/kg AO to mice inoculated with MOS mouse osteosarcoma cells, fluorovisualization of mouse osteosarcoma reached the maximum level. Even a 1-mm-diameter lesion of pulmonary metastasis was visualized. The results suggested that AO may be useful for specific fluorovisualization of human osteosarcomas during surgery.

Acridine Orange↗
PubMed2000

Juxtacortical osteosarcoma. A distinct malignant bone neoplasm.

The purpose of this report is the study of a malignant bone tumor of similar histological picture with conventional (intramedullary) osteosarcoma. Contributing factors in the study of juxtacortical osteosarcoma are the clinical, X-ray and histologic pictures. A case of parosteal osteosarcoma in a 28-year-old male is reported. In conjuction with X-ray findings we review the histological characteristics of the tumor through serial sections of the peripheral, central and parosteal parts and the findings are described in detail. In addition to the histological findings, differential diagnosis and prognosis are also discussed. From the general study of the tumor it has been shown that juxtacortical osteogenic sarcoma behaves differently in contrast to classic osteosarcoma, depending on the degree of differentiation of the tumor.

Adult↗
PubMedDate not supplied

Evaluation of cytotoxic treatment of patients with osteosarcoma by an in vitro chemoresistance assay.

During the previous two decades several assays have been developed aiming to select the most effective chemotherapy regimen for each individual, avoiding the possible toxicity of ineffective drugs. In order to evaluate cytotoxic treatment for patients with osteosarcoma, we applied an in vitro chemoresistance assay by culturing tumour cells and determining their in vitro survival rates after exposure to various chemotherapeutic drugs. The conditions of the assay were optimised in two established osteosarcoma cell lines (KHOS and U2-OS), as compared with data derived after treatment of primary normal adult osteoblasts. Chemotherapeutic drugs (cisplatin, adriamycin or methotrexate or combinations) concentrations were chosen in a range that has been reported to induce tumour cell death in the plasma patients' The method applied successfully in 6 cell cultures originated from biopsies of 7 patients with osteosarcoma and the in vitro response to chemotherapeutic drugs was correlated with the clinical outcome. Such analysis revealed both positive and negative correlation of the in vitro data to the patients clinical responses. Therefore, this study indicated that, although in vitro chemoresistance is a valuable assay, additional analysis and implications of other factors are required for a general evaluation of cytotoxic treatment for patients with osteosarcoma.

Adolescent↗
PubMed1998

Preliminary observation on the correlation between nm23 expression and Ki-67 antigen with early metastasis of human osteosarcoma.

OBJECTIVES: To detect the nm23 expression in osteosarcoma, analyze the correlation between nm23 expression and early metastasis and to study the relation between nm23 expression with tumor differentiation and cell proliferation, as defined by Ki-67 labeling. METHODS: nm23 oncoprotein expression was measured by immunohistochemical staining using formalin fixed, paraffin embedded sections of 39 surgically resected osteosarcomas and was compared with Ki-67 expression, histological findings and early metastasis. In each sample, the grading of immunoreactivity was recorded as 0, 1+, 2+ according to the percentage of nm23 and Ki-67 labeling cells respectively. RESULTS: The cases with more than 25% positive immunoreactivity of nm23 protein were detected in 48.7% of the total cases. There was no statistical difference between nm23 expression and early metastasis, but the cases with nm23 expression appeared to have a trend to get early metastasis. nm23 expression was significantly correlated with Ki-67 expression, which was associated with differentiation of the tumor cells. CONCLUSION: The role of nm23 as a tumor metastasis suppressor in osteosarcoma is less prominent. Both nm23 and Ki-67 may help predict the possibility of early metastasis in human osteosarcomas.

Adolescent↗
PubMed2001

Primary pulmonary osteosarcoma: case report and molecular analysis.

BACKGROUND: Primary pulmonary osteosarcoma is an extremely rare malignancy. To date, only 12 cases have been reported, with a high mortality rate. The authors report on a newly diagnosed patient and describe investigations that were performed using immunohistochemistry and comparative genomic hybridization (CGH). METHODS: The clinical course of a woman age 37 years is presented. Along with routine histologic examination, immunohistochemistry was used to demonstrate differentiation-associated proteins, oncoproteins, and other markers; CGH analysis for genomic alterations; and histochemistry to demonstrate alkaline phosphatase activity. RESULTS: Immunohistochemical analysis showed varying expression patterns using antibodies against a panel of tumor markers. Most notable was high overexpression of BCL-2 and cyclin D. CGH analysis showed that this neoplasm contained a much higher level of genetic aberrations compared with skeletal osteosarcoma. CONCLUSIONS: This tumor exhibited features common to skeletal osteosarcomas but also had some unique features. Genome analysis suggests that this tumor has several genetic aberrations in common with extraskeletal osteosarcoma. The novel regions of instability identified within the tumor genome may contribute toward the unique tumor phenotype and relative chemoresistance.

Adult↗
PubMedDate not supplied

The use of naturally occurring cancer in domestic animals for research into human cancer: general considerations and a review of canine skeletal osteosarcoma.

For many years, research into human cancer has concentrated on human patients and on artificially induced neoplasms in inbred murine hosts. Cancer, however, affects a great variety of mammals, particularly those that have been domesticated. Suchf naturally occurring neoplasms are common in dogs, cats, cattle, horses, etc., and offer fertile ground for studies relating to epidemiologyf, etiology, immunobiology, and therapy. Canine osteosarcoma is described in detail. The clinicopathologic features of this canine tumor closely approximate that of human osteosarcoma and thus make canine osteosarcoma an invaluable comparative model. Canine osteosarcoma and other naturally occurring tumors lie intermediate between the mouse models and human cancer. The use of these veterinary models in the future fabric of cancer research will broaden its base and will influence our conceptual approach to research and clinical options.

Age Factors↗
PubMed2001

Lack of correlation of functional scintigraphy with (99m)technetium-methoxyisobutylisonitrile with histological necrosis following induction chemotherapy or measures of P-glycoprotein expression in high-grade osteosarcoma.

In osteosarcoma, some studies have suggested P-glycoprotein expression is a prognostic factor. The clearance of (99m)technetium hexakis-2-methoxyisobutylisonitrile ((99m)Tc-MIBI) has been used in some tumor systems as an in vivo measure of P-glycoprotein-mediated efflux. In this study we explored the correlation between (99m)Tc-MIBI clearance and histological necrosis following induction chemotherapy and P-glycoprotein expression in osteosarcoma. The primary tumors of 20 patients with high-grade osteosarcoma were imaged at diagnosis with (99m)Tc-MIBI, and the uptake ratios and biological half-lives were calculated. P-Glycoprotein expression in the tumor tissue was determined immunohistochemically and by measuring mRNA expression of the multidrug resistance-1 gene. The histological necrosis following induction chemotherapy was assessed by the Huvos grading system. The biological half-life of (99m)Tc-MIBI ranged from 1.4 to 52.5 h. Seven of the 20 tumor samples had a favorable extent of necrosis following induction chemotherapy. The (99m)Tc-MIBI half-life and uptake ratio showed no correlation with histological necrosis following induction chemotherapy. The (99m)Tc-MIBI half-life and uptake ratio did not correlate with either measure of P-glycoprotein expression. The results of this pilot study indicate that (99m)Tc-MIBI imaging is not an effective predictor of histological necrosis following induction chemotherapy in high-grade osteosarcoma. (99m)Tc-MIBI imaging did not correlate with measures of P-glycoprotein expression in the tumor tissue.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

High-activity samarium-153-EDTMP therapy followed by autologous peripheral blood stem cell support in unresectable osteosarcoma.

PURPOSE: Despite highly efficacious chemotherapy, patients with osteosarcomas still have a poor prognosis if adequate surgical control cannot be obtained. These patients may benefit from therapy with radiolabeled phosphonates. PATIENTS AND METHODS: Six patients (three male, three female; seven to 41 years) with unresectable primary osteosarcoma (n = 3) or unresectable recurrent sites of osteosarcomas (n = 3) were treated with high-activity of Sm-153-EDTMP (150 MBq/kg BW). In all patients autologous peripheral blood stem cells had been collected before Sm-153-EDTMP therapy. RESULTS: No immediate adverse reactions were observed in the patients. In one patient bone pain increased during the first 48 hrs after therapy. Three patients received pain relief. Autologous peripheral blood stem cell reinfusion was performed on day +12 to +27 in all patients to overcome potentially irreversible damage to the hematopoietic stem cells. In three patient external radiotherapy of the primary tumor site was performed after Sm-153-EDTMP therapy and in two of them polychemotherapy was continued. Thirty-six months later one of these patients is still free of progression. Two further patients are still alive. However, they have developed new metastases. The three patients who had no accompanying external radiotherapy, all died of disease progression five to 20 months after therapy. CONCLUSION: These preliminary results show that high-dose Sm-153-EDTMP therapy is feasible and warrants further evaluation of efficacy. The combination with external radiation and polychemotherapy seems to be most promising. Although osteosarcoma is believed to be relatively radioresistant, the total focal dose achieved may delay local progression or even achieve permanent local tumor control in patients with surgically inaccessible primary or relapsing tumors.

Adolescent↗
PubMed2002

Osteosarcoma: a multidisciplinary approach to diagnosis and treatment.

The treatment of osteosarcoma requires a multidisciplinary approach involving the family physician, orthopedic oncologist, medical oncologist, radiologist and pathologist. Osteosarcoma is a mesenchymally derived, high-grade bone sarcoma. It is the third most common malignancy in children and adolescents. The most frequent sites of origin are the distal femur, proximal tibia and proximal humerus. Patients typically present with pain, swelling, localized enlargement of the extremity and, occasionally, pathologic fracture. Most patients present with localized disease. Radiographs commonly demonstrate a mixed sclerotic and lytic lesion arising in the metaphyseal region of the involved bone. Computed tomography and bone scanning are recommended to detect pulmonary and bone metastases, respectively. Before 1970, osteosarcomas were treated with amputation. Survival was poor: 80 percent of patients died from metastatic disease. With the development of induction and adjuvant chemotherapy protocols, advances in surgical techniques and improvements in radiologic staging studies, 90 to 95 percent of patients with osteosarcoma can now be treated with limb-sparing resection and reconstruction. Long-term survival and cure rates have increased to between 60 and 80 percent in patients with localized disease.

Bone Neoplasms↗
PubMedDate not supplied

Hyperthermia increases the susceptibility of chondro- and osteosarcoma cells to natural killer cell-mediated lysis.

As an adjuvant to chemotherapy hyperthermia has proven to be successful as a treatment for osteo- and chondrosarcoma patients. The aim of this study was to investigate whether hyperthermia could increase cellular expression of heat-shock-protein 72 in human osteo- and chondrosarcoma cells and how heat treatment would affect their susceptibility to natural killer cell (NK-cell)-mediated lysis. About 5-10% of the peripheral mononuclear blood cells (PBMC) in the human peripheral blood are natural killer cells (NK-cells). Natural cytotoxicity, mediated by NK-cells, is believed to play an important role in host defense against cancer. The exact mechanisms of recognition of target cells and subsequent NK-cell activation are not yet known. NK-cells, isolated from the peripheral blood of healthy donors, were enriched by magnetic cell-separation to a purity of 85-97%, assessed by FACS-analysis. The susceptibility of heat-treated (42.5 degrees C, 90 minutes) and untreated osteosarcoma (MG63) and chondrosarcoma (HTB94) cell lines to NK-killing was determined by a release assay of lactate dehydrogenase (LDH). Lysis by NK-cells was increased by heat treatment of the target cells from 16.6% + 4.5% to 33% + 15%, p=0.035, for osteosarcoma cells, (E/T ratio of 5:1) and from 13.7% + 3.1% to 27.9% + 16.9%, p=0.021, (E/T ratio of 20:1) for chondrosarcoma cells. An increased expression of HSP72 of chondro- and osteosarcoma cells after heat treatment was detected by the Western blot technique. The results of this study show that hyperthermia increases HSP72 expression in osteo- and chondrosarcoma cells and their susceptibility to NK-cell-mediated lysis. These findings may lead to new therapeutic strategies, using hyperthermia to improve immunological defense against chondro- and osteosarcoma cells.

Bone Neoplasms↗
PubMed2002

Prognostic significance of (18)F-FDG and (99m)Tc-methylene diphosphonate uptake in primary osteosarcoma.

UNLABELLED: The purpose of this retrospective analysis was to evaluate the prognostic significance of both initial glucose metabolism as measured by (18)F-FDG PET and osteoblastic activity as measured by (99m)Tc-methylene diphosphonate (MDP) bone scintigraphy in osteosarcoma. METHODS: In 29 patients (18 male, 11 female; age range, 5-41 y) with primary osteosarcoma, (18)F-FDG uptake and (99m)Tc-MDP uptake were measured semiquantitatively (average and maximum tumor-to-nontumor ratios [T/NT(av) and T/NT(max), respectively]) using PET and bone scintigraphy at the time of diagnosis. After chemotherapy, the patients underwent surgery for their primary tumor, and the response was determined histologically. Cumulative overall survival and event-free survival were determined by clinical and imaging follow-up of 7-72 mo (median, 28 mo). RESULTS: Clinical and imaging follow-up revealed that the disease relapsed or failed to achieve complete remission in 9 patients and that 6 patients died of the disease. Both overall and event-free survival were significantly better in patients with a low (18)F-FDG T/NT(max) (less than the median) than in patients with a high (18)F-FDG T/NT(max) (at least the median). The negative relationship of (18)F-FDG T/NT(av), (99m)Tc-MDP T/NT(max), and (99m)Tc-MDP T/NT(av) with overall and event-free survival did not reach a level of significance. (18)F-FDG uptake values correlated moderately and positively with (99m)Tc-MDP uptake values, but a level of significance was reached only between (18)F-FDG T/NT(max) and (99m)Tc-MDP T/NT(av). CONCLUSION: The initial glucose metabolism of primary osteosarcoma as measured by (18)F-FDG PET using T/NT(max) provides prognostic information. High (18)F-FDG uptake correlates with poor outcome. Thus, (18)F-FDG uptake may be complementary to other well-known factors in judging the prognosis in osteosarcoma.

Adolescent↗
PubMed2001

[Study on in vitro nitric oxide and interleukin-6 levels induced from peripheral mononuclear cells in patients with osteosarcoma].

Peripheral blood mononuclear cells from 32 cases of osteosarcoma and 20 normal controls were separated and induced by lipopolysaccharide, followed by 48 hour incubation in vitro, then the supernatant were collected. The levels of IL-6 were measured by enzyme linked immunosorbent assays, the concentrations of NO were measured by Griess methods. The results were as follows: The concentrations of IL-6 and NO were significantly higher than those in normal controls (P < 0.01). There were positive correlation between the levels of IL-6 and NO in patients with osteosarcoma (r = 0.652, P < 0.01). The results suggest that the immune function of peripheral mononuclear cell in patients with osteosarcoma was disordered. It may activate peripheral mononuclear cells to produce high levels of IL-6 and NO, which may take part in the pathogenesis of osteosarcoma.

Adolescent↗
PubMed2003

99mTc-MIBI imaging as a predictor of therapy response in osteosarcoma compared with multidrug resistance-associated protein and P-glycoprotein expression.

UNLABELLED: In vitro studies have demonstrated that (99m)Tc-methoxyisobutylisonitrile ((99m)Tc-MIBI) is a transport substrate of multidrug resistance (MDR)-related proteins. The aim of this clinical study was to evaluate whether (99m)Tc-MIBI scintigraphy was a functional imaging tool for in vivo detection of multidrug resistance-associated protein (MRP) expression in osteosarcoma and to investigate the role of MRP and (99m)Tc-MIBI imaging to predict the clinical outcome. We also examined whether the scintigraphic parameters would help to distinguish the functional capacity of P-glycoprotein (Pgp) and MRP. METHODS: Twenty-four patients with a diagnosis of osteosarcoma were studied before neoadjuvant chemotherapy. Tumor-to-background ratios of both early (10 min) and delayed (1 h) images and the percentage washout rate (WR%) of (99m)Tc-MIBI were calculated. Immunohistochemical analysis of MRP and Pgp was performed on biopsy specimens, and the response to preoperative chemotherapy was assessed by histopathologic examination. RESULTS: Fifteen of 24 osteosarcoma samples in our series (62.5%) showed significant expression of MRP. The level of MRP expression was significantly correlated with the WR% of (99m)Tc-MIBI (r = 0.58, P = 0.003), and the WR% of (99m)Tc-MIBI was significantly faster in patients with high MRP expression than in those with a low MRP score (P = 0.007). The clearance rate of (99m)Tc-MIBI was significantly slower in tumor samples with negative or low expression of both Pgp and MRP (16% +/- 6.2%) when compared with osteosarcomas with high expression of both proteins (31.7% +/- 8.7%) (P = 0.001). There was not a significant difference between the WR% of (99m)Tc-MIBI in tumors with coexpression of both proteins and in tumors with high expression of either Pgp or MRP. Both the rate of MRP expression and the WR% of (99m)Tc-MIBI were significantly correlated with response rate. CONCLUSION: Our results suggest that the WR% of (99m)Tc-MIBI is correlated with MRP expression. Both the WR% of (99m)Tc-MIBI and MRP expression are correlated with therapy response. (99m)Tc-MIBI can be used as a general probe for functional imaging of both Pgp and MRP; however, it is not capable of differentiating the functional status of either MDR-related glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Apoptotic-resistance of the human osteosarcoma cell line HS-Os-1 to irradiation is converted to apoptotic-susceptibility by hydrogen peroxide: a potent role of hydrogen peroxide as a new radiosensitizer.

In our previous study, we demonstrated that the radioresistance of the human osteosarcoma cell line HS-Os-1, was considered to arise, at least in part, from the low level of ROS formation following irradiation, which in turn may have resulted from the strong scavenging ability of the cells for free radicals, including hydroxyl radicals. Following the study, we found that addition of 1 or 10 mM hydrogen peroxide induced ROS formation, oxidative DNA damage, dysfunction of the mitochondrial membrane potential, and early apoptotic changes in the human osteosarcoma cell line HS-Os-1. We therefore speculated that combined use of irradiation and hydrogen peroxide might exert an additive effect for apoptotic-resistant tumors such as the human osteosarcoma cell line HS-Os-1, in terms of preservation of the radiation-induced hydroxyl radical production supported by the intracellular ROS formation that is induced by exogenous hydrogen peroxide addition. Therefore, in this study, we examined the effect of various doses of irradiation on the existence of 0.1 mM hydrogen peroxide in the culture medium. We found that irradiation with 10 or 20 Gy, under the condition of the presence of 0.1 mM hydrogen peroxide, induced ROS formation, oxidative DNA damage, dysfunction of the mitochondrial membrane potential, and early apoptotic changes in the human osteosarcoma cell line HS-Os-1, though ROS formation and oxidative DNA damage were scarcely seen in response to irradiation of up to 30 Gy, as was shown in our previous study. We therefore concluded that the combined modality of irradiation and such a low concentration of hydrogen peroxide (0.1 mM) is potentially applicable in clinical radiotherapy for many kinds of apoptotic-resistant neoplasms in terms of achieving both local control and improving survival benefit of patients.

Annexin A5↗
PubMedDate not supplied

Methylation status of the retinoblastoma gene (RB1) in osteosarcoma: no evidence for hypermethylation.

Alterations of the retinoblastoma (RB1) tumor suppressor gene are not only associated with retinoblastoma but also with several other malignancies including osteosarcoma. Besides direct sequence alterations, hypermethylation of a CpG island in the promoter region can cause inactivation of the RB1 gene as it has been shown in retinoblastomas. We examined the methylation status of the RB1 gene in 25 osteosarcoma specimens by using the methylation-sensitive restriction enzymes SacII and SmaI. The restriction fragments were hybridized with clone p123, which is a 1.8-kb genomic subclone that spans the RB1 CpG island including the promoter region and exon 1. Whereas we reconfirmed hypermethylation of the RB1 gene in a sporadic retinoblastoma, no hypermethylation could be detected in the 25 osteosarcoma specimens, suggesting that hypermethylation of the RB1 promoter is not of major importance during osteosarcoma genesis.

DNA Methylation↗