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PubMed1993

[A case of osteosarcoma of the rib with bloody pleural effusion].

A case is reported of osteosarcoma of the 11th rib in a 38-year-old woman who presented with dry cough and dyspnea due to bloody pleural effusion and the literature on osteosarcoma of the rib in Japan is reviewed. Osteosarcoma was suggested by roentgenologic findings and examination of a percutaneous needle biopsy specimen. Therefore, we administered chemotherapy, but the tumor showed progressive expansion and invasion, causing paraplegia. The patient died on the 282nd day of admission. We performed an autopsy and diagnosed osteosarcoma histologically. The tumor was covered by a hypervascular capsule, suggesting its association with the bloody pleural effusion. Osteosarcoma of the rib has not been previously reported in association with bloody pleural effusion. Considering the prognosis and characteristics of such tumors, we recommend prompt diagnosis in cases presenting with bloody pleural effusion.

Adult↗
PubMed1993

Cell differentiation in response to partially purified osteosarcoma-derived bone morphogenetic protein in vivo and in vitro.

Bone morphogenetic protein (BMP) and associated noncollagenous proteins (NCP) were isolated from human osteosarcoma tissue. Implantation of 5- and 10-mg samples induced heterotopic ossification in the mouse quadriceps. Osteosarcoma-derived BMP/NCP induced the same process of osteogenesis as human BMP/NCP isolated from bone matrix in vivo. In vitro continuous perfusion of neonatal rat muscle tissue with 5 micrograms/ml osteosarcoma-derived BMP/NCP increased glycosaminoglycan (GAG) synthesis significantly whereas DNA synthesis was relatively unchanged. Similar results were found when muscle tissue was preincubated with 200 micrograms of osteosarcoma-derived BMP/NCP for four hours followed by an incubation period of 14 days in BMP-free medium: GAG synthesis increased significantly, whereas DNA synthesis did not change. The increase in GAG synthesis coincided with cell differentiation but not cell proliferation. Histologic findings confirmed chondrogenesis in vitro. Sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated that osteosarcoma-derived BMP/NCP included a prominent component with a molecular weight of 18,000 d.

Animals↗
PubMed1995

c-fos-induced osteosarcoma formation in transgenic mice: cooperativity with c-jun and the role of endogenous c-fos.

Transgenic mice overexpressing the c-fos proto-oncogene in bone develop osteosarcomas, whereas mice overexpressing c-Jun are normal. In this study, we investigated whether Fos and Jun would cooperate in vivo and whether the threshold levels of Fos are important in osteosarcoma formation. Fos-Jun double-transgenic mice develop osteosarcomas at a higher frequency than single-Fos transgenic mice with no differences in the time of onset of tumor formation. Histological and histochemical analyses indicated that Fos-Jun tumors contained greater quantities of neoplastic bone, were more remodeled, and contained a greater number of multinucleated osteoclast-like cells than tumors isolated from age-matched, single transgenic littermates. In contrast, overexpression of Fos in knockout mice that lack endogenous Fos resulted in a decrease in the number of tumor-bearing mice; osteosarcomas were almost absent in c-fos -/- mice, whereas tumor incidence was reduced to approximately 50% in c-fos +/- mice. Cell lines isolated from Fos-Jun transgenic tumors expressed high levels of both transgenes but significantly lower levels of the jun-related gene junB compared with cells expressing only a c-fos transgene. Osteoblastic marker genes were expressed at varying levels in different cell lines, but expression of interstitial collagenase (matrix metalloproteinase-1) was enhanced in cells derived from Fos-Jun tumors. These studies demonstrate that coexpression of a c-jun transgene can enhance Fos-induced oncogenesis in vivo and suggest that a critical level of Fos is necessary for osteosarcoma development.

Animals↗
PubMed1997

Histological and immunohistochemical diversities, and proliferative activity and grading in osteosarcomas.

To examine the differentiation and proliferative activity of tumor cells, 30 osteosarcomas, including osteoblastic, chondroblastic, fibroblastic, malignant fibrous histiocytoma-like, telangiectatic, giant cell-rich low-grade central, and epithelioid types, were studied immunohistochemically. A variable number of tumor cells in all cases showed osteocalcin immunoreactivity. In four preparations of the frozen sections, osteoblastic, fibroblastic, and chondroblastic tumor cells were positive for bone-type alkaline phosphatase antibody 2D3. S-100 protein immunoreactivity was found not only in seven tumors of the chondroblastic type, but also in four of nine osteoblastic tumors and each of the low-grade central, giant cell-rich, and epithelioid types. A histiocytic marker, CD68, was negative for tumor cells in all cases. Some cells of 17 tumors were positive for desmin and/or alpha-smooth muscle actin; this was regarded as an indication of myofibroblastic differentiation. Tumor cells of the epithelioid type and those of two osteoblastic tumors expressed cytokeratin (CAM5.2) and epithelial membrane antigen. Proliferating-cell nuclear antigen (PCNA) reactivity was found in the cell nuclei of 22 tumors, most of which were high grade. Many cells in six high-grade tumors also showed the nuclear staining for p53 protein. Of these tumors, PCNA and p53 positivities tended to be more numerous in osteoblastic cells, atypical spindle-shaped, and bizarre giant cells than in well-developed chondroid cells. From these findings, osteosarcomas are concluded to be composed basically of osteoblastic cells, that are indispensable for diagnosis of osteosarcomas, with a variable number of chondroblastic, myofibroblastic, and, rarely, epithelioid cells, and this manifold cellular differentiation corresponds to the histological and clinical diversities. The osteoblastic, fibro- or myofibroblastic, and undifferentiated cells mainly participate in proliferation of osteosarcomas. The p53 gene alterations may play a part in the neoplastic transformation and proliferation of osteosarcomas.

Alkaline Phosphatase↗
PubMedDate not supplied

Maxillary metastasis of osteosarcoma.

Osteosarcoma, either primary or metastatic, rarely involves the jaws. Though only a few cases of mandibular metastasis of osteosarcoma have been reported, only one case of et al maxillary involvement (Singh, 1978) has been reported. A case of 21 year old boy with metastasis of osteosarcoma to the right maxilla from primary osteosarcoma of the left femur is presented. The patient complained of pain and swelling in the left maxillary region which was earlier diagnosed as maxillary sinusitis on the basis of Water's sinus radiograph in a medical hospital. Further radiographic examination with the panoramic and intraoral periapical radiographs done by us and later by fine needle aspiration cytology led us to diagnose a secondary deposits of osteosarcoma.

Adult↗
PubMedDate not supplied

Avoidance of doxorubicin resistance in osteosarcoma cells using a new quinoline derivative, MS-209.

P-glycoprotein (Pgp), a membrane drug efflux pump, is thought to be responsible for the observed drug resistance in osteosarcoma. We have recently developed Pgp-positive, multidrug resistant (MDR) murine osteosarcoma cell lines, which may be suitable models for the study of drug resistance in osteosarcoma. In this study, we investigated the effect of a newly synthesized quinoline compound, MS-209, on the reversal of doxorubicin (DOX) resistance in these cell lines. Three different types of resistance modifying agents (RMAs) as well as MS-209 were studied. These included the calcium channel blocker verapamil, and the immunosuppressive agents cyclosporin A and FK506. The reversal effects of the RMAs on DOX resistance were assessed by the MTT assay. In the absence of RMAs, the MDR osteosarcoma cells were 20-fold more resistant to DOX than the parental cells. When MS-209 was added at a final concentration of 0.1 to 3 microM to the MDR cells, 3-to 74-fold sensitization was observed. A complete reversal (37-fold sensitization) of the resistance was obtained at 1 microM MS-209. This concentration of MS-209 was 3-, 8- and 28-fold more effective than the same concentration of FK506, verapamil and cyclosporin A, respectively. These results indicate that MS-209 may be a more effective RMA, and that DOX resistance in osteosarcoma cells could be reversed by comparatively low doses of MS-209.

Antineoplastic Agents↗
PubMed1998

Antitumor activity of TP3(anti-p80)-pokeweed antiviral protein immunotoxin in hamster cheek pouch and severe combined immunodeficient mouse xenograft models of human osteosarcoma.

TP3-pokeweed antiviral protein (PAP) immunotoxin is directed against the p80 antigen on osteosarcoma cells. Previous studies have demonstrated that TP3-PAP kills clonogenic human osteosarcoma cells in vitro and shows significant antitumor activity in a murine soft tissue sarcoma model (P. M. Anderson, et al, Cancer Res., 55: 1321-1327, 1995.) In this study, we demonstrate that TP3-PAP elicits potent in vivo antitumor activity in a hamster cheek pouch model of human osteosarcoma. Furthermore, treatment with TP3-PAP at nontoxic dose levels significantly delayed the emergence and progression of leg tumors and markedly improved tumor-free survival in severe combined immunodeficient mice challenged with OHS human osteosarcoma cells. Thus, TP3-PAP may be useful in the treatment of poor risk osteosarcoma.

Animals↗
PubMed1998

Expression of functional CD40 on human osteosarcoma and Ewing's sarcoma cells.

CD40, a membrane glycoprotein of the tumor necrosis factor receptor family, is expressed by several tumor types, including B-cell lymphomas, carcinomas, and melanoma, but little is known concerning its expression by sarcoma. We used flow cytometry to analyze the expression of CD40 in human cell lines derived from 12 osteosarcomas, 6 Ewing's sarcomas, and 5 rhabdomyosarcomas. Detectable CD40 levels ranging from low to very high were found in one-third of osteosarcomas, whereas five of six Ewing's sarcomas expressed intermediate levels of CD40; all rhabdomyosarcomas were CD40-negative. At the tissue level, two of eight primary high-grade osteosarcomas showed CD40-positive immunostaining. Osteosarcoma cells and Ewing's sarcoma cells expressing CD40 were treated with recombinant soluble CD40 ligand to analyze CD40 function. Treatment with soluble CD40 ligand increased the level of apoptotic cells and stimulated the transcription of matrix metalloproteinase 9 gene, enhancing matrix metalloproteinase 9 enzyme secretion. The results indicate that in human osteosarcoma and Ewing's sarcoma, CD40 is a functional receptor whose engagement can have opposite effects on tumor cell survival and malignancy.

Apoptosis↗
PubMed2006

Outcome of patients with osteosarcoma over 40 years of age: is angiogenesis a marker of survival?

BACKGROUND: Osteosarcoma predominantly afflicts young people in their second and third decades of life. When osteosarcoma arises in patients older than 40 years, the prognosis is usually poorer compared to their younger counterparts. Although the clinical, histopathologic features and prognostic indicators are well defined for young patients, much less is known about affected adults. The purpose of this study is to describe our institution's experience with the management of osteosarcoma in patients greater than 40 years and also evaluate, by immunohistochemical analysis, the prognostic significance of microvessel density, as a marker of intratumoural angiogenesis. METHODS: A retrospective clinicopathological analysis was performed on 11 patients over the age of 40 years that were treated at our institution between 1996 and 2004. Archival pre-treatment biopsy tissue was retrieved for immunohistochemical staining against two endothelial cell markers (CD31 and CD34) and also against VEGF. Angiogenesis was assessed by determining the intratumoural microvessel density (MVD) and the degree of VEGF expression in these specimens. This was correlated with patient outcome in terms of local recurrence, metastasis and death. Histological results were also compared to a group of patients less than 40 years of age. RESULTS: Of the 11 patients, 9 were male and 2 were female and the mean age was 58 years (range, 42-85). In 7 patients, osteosarcoma arose secondarily from Paget's disease of the bone. The most common site involved was the humerus (7) followed by the femur (2) then pelvis (1) and ulna (1). At the time of diagnosis, 4 patients had metastatic disease. Preoperative chemotherapy was given to 4 patients, with a good response in 3 patients. Six patients underwent limb-sparing surgery, 4 had amputations and 1 was treated with radiotherapy alone. The mean follow up time was 31.5 months (range, 8-81). At this time, 4 patients (36%) had developed lung metastases and 5 patients (46%) had died. Overall survival was 54.5%. Intratumoural MVD was higher in patients over 40 years, although not statistically significant (p = 0.111, CD31; p = 0.134, CD34). VEGF was uniformly expressed in all sections, however no relationship was found between the degree of expression and patient age. CONCLUSION: The prognosis for older patients with osteosarcoma is generally poor. Initial presentation is commonly associated with metastatic disease and neoadjuvant chemotherapy is often avoided because of its side effects. Increased intratumoural vascularity may contribute to the poorer prognosis in these patients, however further studies are needed.

Journal Article↗
PubMed1982

Periosteal chondrosarcoma and periosteal osteosarcoma. Two distinct entities.

This review of 27 cases serves to emphasis that periosteal chondrosarcoma and periosteal osteosarcoma are two distinct entities. Clinically, periosteal chondrosarcoma is less painful than periosteal osteosarcoma and runs a slower course. Radiographically, periosteal chondrosarcoma tends to affect the metaphysis and contains granular or "popcorn" opacities; while periosteal osteosarcoma more often affects the mid-diaphysis and shows lytic lesions with some spicules of reactive bone perpendicular to the underlying cortex. Histologically, periosteal chondrosarcoma shows lobular well-differentiated cartilage with Grade I or II (rarely Grade III) malignancy; periosteal osteosarcoma has a chondroid matrix with some osteoid component and Grade II or III malignancy. The prognosis in periosteal chondrosarcoma is good; conservative surgery is usually effective and metastases are very uncommon. In periosteal osteosarcoma the prognosis is less satisfactory but is better than that of other osteosarcomata; wide surgical excision is, however, needed and the incidence of metastases is about 15 per cent.

Adolescent↗
PubMed2001

The effect of local recurrence on survival in resected osteosarcoma.

The aim of this study was to assess the effect of local recurrence on survival in primary osteosarcoma. 559 patients entered into two randomised trials of the European Osteosarcoma Intergroup who received surgery for primary operable high-grade osteosarcoma of the extremities were included in this analysis. Proportional hazards modelling techniques were used to assess the relative importance of sex, age, site, surgery performed and local recurrence. The last of these was considered as a time-dependent covariate. 42/559 (8%) patients had a local recurrence. In the multivariate analysis, local recurrence was found to greatly increase the risk of death (hazard ratio (HR)=5.10, 95% confidence interval (CI) 3.51-7.41). Site and surgery performed also had a significant influence within this model. Using the technique of landmark analysis, with the landmark time set at 18 months, local recurrence alone had a significant influence on survival (HR=4.60, 95% CI 2.80-7.57). Local recurrence is an indicator of poorer survival for patients with operable primary osteosarcoma.

Adolescent↗
PubMed2004

Osteosarcoma of the jaws in children.

Two cases of osteosarcoma of the jaws in children are reported. One patient was a 13-year-old girl whose first symptoms included nasal and maxillary sinus congestion, followed by epistaxis. She was found to have chondroblastic osteosarcoma extending through the left maxillary alveolar process and sinus. Following surgery and chemotherapy, the patient has been free of disease for 7 years. The second patient, an 8-year-old boy, was diagnosed with juxtacortical (parosteal) osteosarcoma of the mandible, which is a less aggressive variant of the neoplasm. It is believed that this is the youngest patient reported to date with juxtacortical osteosarcoma of the jaws. He was treated by block resection of the right side of the mandible and is free of disease 3(1/2) years later.

Adolescent↗
PubMed1998

Expression of insulin-like growth factor receptor, IGF-1, and IGF-2 in primary and metastatic osteosarcoma.

BACKGROUND AND OBJECTIVES: We have previously shown that insulin-like growth factor (IGF)-responsive murine sarcomas demonstrate inhibition of local and metastatic disease growth when implanted in an IGF-deficient host animal. In this experiment, we tested whether IGF receptor (IGF-R) and ligands were expressed in human primary and metastatic osteosarcomas. METHODS: Fifty-two specimens of human osteosarcoma tumor from 48 patients were assayed for IGF-R, IGF-1, and IGF-2 using reverse transcriptase polymerase chain reaction. RESULTS: Twenty-one of 46 tumors analyzed had levels of expression of IGF-R greater than or equal to the positive control cell line. Twenty-seven of 44 expressed levels of IGF-1 greater than or equal to the positive control, as did 21 of 38 cases assayed for IGF-2. No differences were found between 40 primary tumor samples and 12 metastatic lesions in mean levels of IGF-R, IGF-1, or IGF-2. There was a moderately strong correlation between expression of IGF-R and IGF-1, suggesting that autocrine stimulation may be an important mechanism for stimulation of osteosarcoma proliferation. CONCLUSIONS: A significant proportion of osteosarcoma tumors express IGF-R and ligands. Higher levels of expression were not correlated with metastatic lesions.

Bone Neoplasms↗
PubMed1997

Overexpression of resistance-related proteins (metallothioneins, glutathione-S-transferase pi, heat shock protein 27, and lung resistance-related protein) in osteosarcoma. Relationship with poor prognosis.

BACKGROUND: The prognosis for patients with osteosarcoma has improved over the past 20 years, mainly due to developments in chemotherapy. Some proteins have been reported to show drug resistance. Theoretically, overexpression of some of these proteins makes treatment difficult, leading to poorer outcome. METHODS: Specimens taken from conventional osteosarcomas of the extremity bones from 60 patients younger than 30 years were used. In all cases, preoperative oncostatic chemotherapy was undertaken after biopsy. If available, biopsy specimens were also used for sequential comparison. Among resistance-related proteins, expression of metallothioneins (MTs), glutathione-S-transferase pi (GST pi), heat shock protein 27 (Hsp27), and lung resistance-related protein (LRP) was evaluated immunohistochemically in paraffin sections. The log rank test was used for univariate analysis and the Cox regression model for multivariate analysis. RESULTS: At biopsy, only overexpression of Hsp27 was associated with poor prognosis. At surgery, a relationship was observed between poor prognosis and overexpression of GST pi, Hsp27, and LRP. Groups overexpressing one protein tended to overexpress another. Overexpression of these proteins in surgical specimens also correlated with histologic response to preoperative chemotherapy and clinical stage. In multivariate analysis, Hsp27 overexpression at biopsy was an independent prognostic factor. CONCLUSIONS: Inherent overexpression of Hsp27 is independently related to poor outcome in osteosarcoma patients. Overexpression of GST pi, Hsp27, and LRP at surgery might be associated with failure of preoperative chemotherapy. Control of the expression of these proteins may improve the outcome for patients with osteosarcoma.

Adolescent↗
PubMed1997

B7-1-transfected tumor vaccine counteracts chemotherapy-induced immunosuppression and prolongs the survival of rats bearing highly metastatic osteosarcoma cells.

To investigate the therapeutic efficacy of B7-1-expressing tumor vaccine on metastatic osteosarcoma, we introduced mouse B7-1 cDNA into a rat osteosarcoma cell line, MSK-8G. Flow cytometric analysis confirmed that the transfectants designated as B7-1-8G 10-1 and B7-1-8G 15-5 stably expressed B7-1 molecules on the cell surface. B7-1 transfectants were not only rejected by immunocompetent F344 rats but also conferred systemic immunity that protected against challenge with B7-negative parental osteosarcoma cells. In contrast, T-cell-deficient nude rats failed to reject B7-1 transfectants, indicating that T cells play a major role in the development of systemic immunity. We then conducted experimental therapies using irradiated B7-1-transfected tumor vaccine and methotrexate in an orthotopic implantation model. B7-1-transfected tumor vaccine significantly reduced the number of pulmonary metastatic nodules. Moreover, the combination of methotrexate and tumor vaccine further decreased the number of pulmonary metastatic nodules. Most important, the combined therapy with methotrexate and tumor vaccine resulted in a tumor-free condition as judged by the histopathological absence of tumors and survival of rats for more than 180 days. Furthermore, B7-1-transfected tumor vaccine could counteract the immunosuppressive effect of methotrexate. These findings strongly suggest that the B7-1-transfected tumor vaccine may be of clinical value for patients with metastatic osteosarcoma who exhibit immunosuppression due to chemotherapy.

Animals↗
PubMed1997

SV40 DNA in human osteosarcomas shows sequence variation among T-antigen genes.

Authentic simian virus 40 (SV40) has been detected in association with human choroid plexus and ependymoma tumors, and SV40-like DNA sequences have been found in some human osteosarcomas. We report here an analysis of human osteosarcoma samples for the presence of SV40 DNA using PCR and primers directed at 4 distinct sites of the SV40 genome, coupled with sequence analysis. Authentic SV40 DNA sequences were detected in 5 of 10 osteosarcoma tumor samples. The SV40 regulatory region in each case was identical and of archetypal length (non-duplicated enhancer), as is usually found in natural isolates of SV40 from monkeys and in human brain tumors. A section of the gene that encodes a viral late gene product (VP1) was detected in 5 of 10 tumors and had an exact match with the known sequence of SV40. Two separated segments of the large T-antigen (T-ag) gene were found in the same 5 tumors. Analysis of the DNA sequences encoding the T-ag carboxy terminus revealed sequence variation among the tumors, as observed previously in viral DNA associated with human brain tumors. There does not appear to be a preferential association of a T-ag variable domain sequence with a given tumor type. No sequences from the regulatory region of human polyomaviruses JCV and BKV were detected in the bone tumors. We also noted less efficient recovery of SV40 DNA from tumor samples fixed in paraffin as compared to frozen tumors. Our results confirm the presence of SV40 DNA in human bone tumors and, based on the sequence variation observed for the carboxy terminus of the T-ag gene, suggest that there is not a specific SV40 strain associated with human osteosarcomas.

Adolescent↗
PubMed1997

Head and neck osteosarcoma at the University of Washington.

BACKGROUND: Head and neck osteosarcoma is a comparatively rare and aggressive malignancy. Our goal was to examine the experience of head and neck osteosarcoma patients seen over a 15-year period at the University of Washington Medical Center and compare this with the published experience of other centers in terms of demographics, histology, treatment, and survival rate. METHODS: We reviewed surgical pathology slides and clinical treatment records of 13 patients who were treated at the University of Washington Medical Center between 1981 and 1996. A total of 17 cases from 13 patients (13 primary tumors and 4 recurrences) were studied. RESULTS: There was a slight male predominance, with a male:female ratio of 1.6:1, and median age at diagnosis of 40.9 years (range 22 to 75 years), both slightly higher than has been generally reported. Three of 13 patients had recognized risk factors for the development of osteosarcoma: 2 with a history of prior radiotherapy and 1 with Paget's disease. All surgical pathology specimens were examined independently by two pathologists for histologic grading and typing. At initial presentation, 9/13 (69%) cases had conventional (osteoblastic) histology; 2/13 (15%) were fibroblastic, 1 chondroblastic (8%) and 1 parosteal (8%). Eight of 13 (62%) cases were high grade at initial presentation. Four of 13 (30%) of the primary tumors were low grade 2, of which did not recur over a median follow-up period of 24 months. The other 2 low-grade tumors later recurred locally, as high-grade osteosarcomas, after disease-free intervals of 1 year and 14 years, respectively. One patient had an intermediate-grade tumor which has not recurred as of last follow-up. Combined-modality treatment, including surgery with or without radiotherapy and/or chemotherapy, was given depending on the histologic grade, surgical margins, and recurrence. Some patients with low-grade tumors had surgery only. There were 5 local recurrences, 1 of these following a disease-free interval of 14 years. One patient had 3 separate recurrences at the same site. Ten of 13 (77%) are alive and disease-free. Of the 3 deaths, 1 was related to radiation-induced brain necrosis, without evidence of recurrent tumor. The project 5-year overall survival in this series is 72%, with a mean follow-up of 58 months (median, 36 months). Of those receiving neoadjuvant chemotherapy, 6/7 have survived to the present. CONCLUSION: Given the limitations of a small patient population, our data suggest that neoadjuvant chemotherapy may provide benefit in terms of survival. Longer follow-up will be necessary to support this conclusion. Our data also show that our population has a higher-than-average age of onset, low presence of risk factors, and better survival rate in comparison with the published series from other institutions.

Adult↗
PubMed1975

A laboratory model for the study of the immunobiology of osteosarcoma.

Inoculation of Moloney sarcoma virus into the marrow cavity of the tibia of newborn Wistar-Lewis rats resulted in the appearance of an initially localized osteosarcoma in 97.7% of these animals. At least 77.9% of the rats developed lung metastases and died, usually within 6 weeks of inoculation. The remaining 22.1% showed regression of disease after initial growth of the tumor. Tumor cells were maintained in tissue culture and used as target cells for a visual and isotopic (3H-thymidine or 125IUdR) microcytotoxicity assay. Cell-mediated immunity could be measured by these methods throughout the course of the illness in animals with progressive disease as well as in those whose tumors eventually regressed. The presence of serum factors capable of modifying the level of CMI was documented. This Moloney-sarcoma-virus-induced rat osteosarcoma and human osteosarcoma thus appear to have several basic pathologic and immunologic similarities. The model may be useful for studying the effects of a variety of treatment protocols upon the clinical course and immune response to osteosarcoma.

Animals↗