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PubMed2001

The IGFBP-3 mRNA and protein levels are IGF-I-dependent and GH-independent in MG-63 human osteosarcoma cells.

Growth Hormone (GH), Insulin-like Growth Factors (IGFs) and IGF-Binding Proteins which modulate the IGFs' bioavailability (e.g. IGFBP-3, -4, -5), are essential regulators of bone remodeling. In this study, MG-63 human osteosarcoma cells were used as a model system to investigate the mechanism(s) whereby IGF-I and GH control IGFBP-3 gene expression. Physiological concentrations of IGF-I (1-20 nM) induced a dose-dependent increase in the steady-state amount of IGFBP-3 mRNA (maximal stimulation: approximately 9-10-fold). This increase was detectable 3 h after the onset of IGF-I treatment, was enhanced over a 24 h period, then plateaued until at least 30 h. Consistently, a dose-dependent increase in IGFBP-3 secretion ( approximately 40-50-fold at IGF-I concentrations>/=16 nM) was observed by western ligand- and immuno-blot analysis of MG-63 cells conditioned medium, and its time course was similar to that observed for IGFBP-3 transcripts. IGFBP-3 mRNA stability (t(1/2) approximately 20 h) was identical in the presence or absence of IGF-I treatment. By contrast, human (h) GH treatment (24-72 h) of MG-63 cells did not increase IGFBP-3 secretion in the conditioned medium. Ectopic expression of recombinant rat GH-R resulted in hGH-enhanced expression of GH-responsive reporter gene constructs, but did not increase endogenous IGFBP-3 gene expression, suggesting that the GH unresponsiveness was not only due to the very low level of GH binding sites at the plasma membrane level. Altogether, these results support the conclusions that in MG-63 cells (i) transcriptional rather post-transcriptional mechanisms are involved in the IGF-I-induced increase of IGFBP-3; (ii) the abundance of GH-R is very low at the plasma membrane level; (iii) the dowstream GH-signaling cascade is fully functional in this human osteosarcoma cell line; and (iv) the endogenous IGFBP-3 gene is not responsive to hGH in human MG-63 osteosarcoma cells.

Culture Media, Conditioned↗
PubMed1998

Actin organization associated with the expression of multidrug resistant phenotype in osteosarcoma cells and the effect of actin depolymerization on drug resistance.

We have previously reported that P-glycoprotein (Pgp)-overexpressing multidrug resistant (MDR) osteosarcoma cells were functionally more differentiated than their parent cells. The present study showed that in the parent cells, the actin filaments were sparsely distributed or were diffusely spread throughout the cytoplasm, whereas the MDR osteosarcoma cells exhibited a remarkable increase in well-organized actin stress fibers. Furthermore, dihydrocytochalasin B, a specific inhibitor of actin polymerization, dramatically disrupted this network of stress fibers, increased the intracellular accumulation of doxorubicin (DOX) and modified the resistance against DOX. These results indicate that the organization of actin filaments associated with cellular differentiation may be involved in the expression of Pgp function in the MDR osteosarcoma cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Heterogeneous pattern of gene expression in cloned cell lines established from a rat transplantable osteosarcoma lung metastatic nodule.

We have established three cloned cell lines (COS1NR, COS2NR and COS4NR) from the lung metastatic nodule of a highly metastatic variant of rat transplantable osteosarcoma, C-SLM. All three clones shared the same morphological characteristics and tumorigenicity, but their growth rates in vitro and metastatic ability in vivo differed from each other. Single-strand conformation polymorphism (SSCP) analysis revealed all three clones to have the same p53 gene mutation and parent C-SLM tumor. On the other hand, Northern blot analysis showed a different pattern of expression for the genes, c-fos, c-jun, c-Ha-ras, transin (rat stromelysin), bone Gla protein (osteocalsin) and nm23/NDP kinase. These results indicate the presence of a heterogeneous cell population in terms of the different pattern of gene expression in a lung metastatic nodule of rat osteosarcoma and the present newly established cell lines will be useful for further investigation of the biological behavior of osteosarcomas.

Animals↗
PubMed1997

Melatonin in osteosarcoma: an effective drug?

The pineal indole amine melatonin has been shown to have oncostatic properties in a wide variety of neoplasms. Melatonin levels start to diminish before the onset of puberty and continue to decline during puberty. There appears to be a relationship between the rate of bone growth and the incidence of osteosarcoma (which was found to be highest in the long bones of the leg in the 10-14-year age group). It is hypothesized that the simultaneous decrease in melatonin levels (with diminishing oncostatic protection), concurrent with the exponential increase in bone growth during puberty (i.e. increased rate of cell proliferation), could be a factor in the typical age distribution of osteosarcoma. Melatonin is of value in combined chemotherapy, because it is non-toxic and can augment the anti-cancer action and decrease the side-effects of many other chemotherapeutic drugs. It is hoped that melatonin, as an adjunct to the routine chemotherapy of osteosarcoma, will help to improve the prognosis of this too often fatal disease.

Adolescent↗
PubMed1998

Clinicopathologic implications of MDM2, p53 and K-ras gene alterations in osteosarcomas: MDM2 amplification and p53 mutations found in progressive tumors.

It is widely recognized that various oncogenes and tumor suppressor genes contribute to tumorigenesis and progression of osteosarcomas. However, whether genetic alternations enable us to predict the prognosis of patients with osteosarcomas is unclear. Southern blotting and polymerase chain reaction/single strand conformation polymorphism (PCR-SSCP) analyses were performed to search for MDM2, ras family and p53 gene alterations in 17 patients with high-grade osteosarcomas. Amplification of the MDM2 gene was found in three tumors, two of which were obtained from a regional lymph node metastasis and the other from a locally advanced lesion. Point mutations of the p53 gene were found in exons 4 and 5 in two tumors each. One of the four tumors with p53 mutations was obtained from a lymph node metastasis, one from a recurrent tumor and another from the primary tumor of a patient who developed lung metastases. Coexistence of MDM2 amplification with point mutation of the p53 gene was observed in two tumors. A point mutation of the K-ras oncogene was detected at codon 13 in two tumors. MDM2 amplification and p53 mutation may reflect tumor progression, although no correlation between alteration and response to chemotherapy or patient survival was demonstrated.

Adolescent↗
PubMed1999

Hepatic angiomyolipoma in a 26-year-old Caucasian woman with a history of tibial osteosarcoma.

We report on a 26-year-old Caucasian woman who was referred to the Department of Surgery complaining of general malaise, feeling of fullness with occasional vomiting and intermittent jaundice. The patient had previously suffered from tibial osteosarcoma of the left leg which was resected 13 years ago and subsequently treated with radiation and chemotherapy. During clinical investigations a 12 x 12 x 6.5 cm large mass was found in the left lobe of the liver. This was resected, and subsequently shown to be a sporadic hepatic angiomyolipoma. In order to investigate a possible link between the two tumours, we investigated mutations in the p53-gene, loss of heterozygosity (LOH) at p53, Rb and p16, c-Myc expression, and the telomerase activity of the angiomyolipoma and the osteosarcoma. Whilst the tibial osteosarcoma showed LOH at p16, no genetic alterations or increased telomerase activity were found in the angiomyolipoma. The occurrence of both these tumours in this patient is therefore probably a coincidence.

Adult↗
PubMed2001

Definitive intraoperative very high-dose radiotherapy for localized osteosarcoma in the extremities.

PURPOSE: To evaluate the outcome and adverse effects in patients with osteosarcoma treated with very high-dose definitive intraoperative radiotherapy (IORT), with the intention of saving the affected limb. METHODS AND MATERIALS: Thirty-nine patients with osteosarcoma in their extremities were treated with definitive IORT. The irradiation field included the tumor plus an adequate wide margin and excluded the major vessels and nerves. Forty-five to 80 Gy of electrons or X-rays were delivered. The median follow-up of the surviving patients was 124 months. RESULTS: The cause-specific and relapse-free 5-year survival rate was 50% and 43%, respectively. Distant metastasis developed in 23 patients; 19 died and 4 were alive for >10 years. Nine local recurrences were found 4-29 months after IORT in the affected limb. No radiation-induced skin reaction or nerve palsy was observed in the patients treated with X-rays. Experiments using phantoms also confirmed that the scatter dose was below the toxic level in the IORT setting with X-rays. CONCLUSIONS: Very high-dose definitive IORT combined with preventive nailing and chemotherapy appeared to be a promising quality-of-life-oriented alternative to treating patients with osteosarcomas in the extremities, although the problem of recurrences from the surrounding unirradiated soft tissue remains to be solved.

Adolescent↗
PubMed1996

Isolated limb perfusion with TNF alpha and melphalan in a rat osteosarcoma model: a new anti-tumour approach.

Isolated limb perfusion (ILP) with TNF alpha, IFN gamma and melphalan causes impressive tumour reduction in patients with irresectable soft tissue sarcomas with a high limb salvage rate. Since this therapy could be of value in patients with progressive osteosarcoma, we performed a study in an osteosarcoma tumour model in the rat. The ROS-1 osteosarcoma was implanted s.c. in the hind leg of WAG rats. Rats were divided in four groups: rats that underwent ILP with perfusate alone, TNF alpha alone, melphalan alone or their combination. Almost all rats, treated with a sham ILP or a perfusion with 40 micrograms melphalan, showed progressive disease (PD) (6/6 and 5/6). After perfusion with 50 micrograms TNF alpha alone a varied response was observed: 2/6 PD, 2/6 no change (NC) and 2/6 a complete remission (CR). After combined perfusion: 3/6 rats had a partial remission and 3/6 a CR. The best and most consistent responses are obtained by combining TNF alpha and melphalan. The discrepancy with the in vitro sensitivity of ROS-1 indicates that indirect effects are important in this tumour model.

Animals↗
PubMedDate not supplied

Metachronous multifocal osteosarcoma: a case report and literature review.

Metachronous multifocal osteosarcoma (MFOS) is a rare form of osteosarcoma manifested by one or more new tumors developing after the initial treatment of primary osteosarcoma. The pathogenesis of metachronous MFOS is still obscure whether it represents multiple true primaries or metastatic disease. However, there is a clinical significance that metachronous MFOS is a potentially curable disease [Resnick D, Kyriacos M, Greenway GD. Tumors and tumor-like lesions of bone: imaging and pathology of specific lesions. In: Resnick D, editor. Diagnosis of bone and joint disorders. Philadelphia: Saunders, 1995: p. 3697-9.]. To our knowledge, there have been only a few reports about metachronous MFOS. We report a case of MFOS in a 14-year-old boy with review of the literature.

Adolescent↗
PubMedDate not supplied

Imaging findings of extrapulmonary metastases of osteosarcoma.

PURPOSE: To review imaging findings of extrapulmonary metastasis from osteosarcoma and to evaluate them for any consistent pattern and correlation between imaging findings. MATERIALS AND METHODS: This study was retrospectively conducted in 13 patients with extrapulmonary metastasis of pathologically confirmed osteosarcoma. We evaluated the radioisotope (RI) scans (n=16), ultrasonography (USG) (n=4), computed tomography (CT) scans (n=10), MRIs (n=6), clinical records, and pathological reports for assessment of imaging findings and correlation between radiologic findings and RI uptake of the lesions. Points evaluated were the following: uptake on RI scans, presence of mineralization on CT, and MRI, size, enhancement pattern, attenuation on CT, signal intensity (SI) on MRI, and echogenicity on USG. RESULTS: Extrapulmonary metastatic sites were diverse, including another bone other than the primary site (n=6), lymph node (n=4), pleura (n=2), liver (n=2), pancreas (n=1), kidney (n=1), peritoneum (n=1), muscle (n=1), and subcutaneous fat layer (n=1). One patient had tumor growth within the pulmonary artery and jejunum. Among 21 metastatic sites in 13 patients, bone scan was performed in 16 cases and RI uptake was detected in 10 lesions. Calcification was detected in eight lesions on radiologic imaging, including plain radiography, USG, CT, and MRI. Two lesions showed RI uptake without definite calcification or ossification on MRI and plain radiography, respectively. We analyzed the enhancement pattern and mass size in 18 metastatic sites and these factors had poor correlation with uptake on RI scans. CONCLUSION: The sites and imaging findings of extrapulmonary metastasis of osteosarcoma were variable. All the lesions with mineralization were detectable on RI scans prior to radiologic imaging. RI scan has a limited role in the evaluation of metastatic lesions without mineralization.

Adipose Tissue↗
PubMed2003

Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders.

From 1990 to 1997, 113 eligible patients with classical osteosarcoma received neo-adjuvant chemotherapy consisting of high-dose methotrexate, cisplatin and doxorubicin. Good histological responders continued to receive the same therapy postoperatively, while poor responders received salvage therapy with an etoposide/ifosfamide combination. With a median follow-up of 83 months, the projected metastasis-free and overall survival rates at 5 years are 63 and 74%, respectively. Independent favourable prognostic factors for outcome were tumour volume < 190 ml, 24-h serum methotrexate > 4.5 microM and female gender. The etoposide/ifosfamide replacement combination did not improve outcome in the poor histological responders. In conclusion, this intensive multi-agent chemotherapy results in > 70% of patients with classical osteosarcoma surviving for 5 years. The data obtained from this non-randomised study do not support discontinuation and exchange of all drugs used preoperatively in histological poor responders. As observed in previous Scandinavian osteosarcoma studies, female gender appears to be a strong predictor of a favourable outcome.

Adolescent↗
PubMed2006

Expression of estrogen receptors alfa and beta mRNA and alkaline phosphatase in the differentiation of osteoblasts from elderly postmenopausal women: comparison with osteoblasts from osteosarcoma cell lines.

OBJECTIVE: To evaluate the expression of estrogen receptors (ER) alpha and beta, and activity of alkaline phosphatase during differentiation of primary osteoblast cells (hOB) from aged postmenopausal women and human osteosarcoma cell lines (HOS, MG63). MATERIALS AND METHODS: Osteoblast cultures were prepared from the upper femur of postmenopausal patients (age, 60-74 years) and HOS. At the indicated times (days 5, 10, 15, 20, and 25), alkaline phosphatase activity and expression of ERalpha and ERbeta mRNA were evaluated. RESULTS: In both cultures of primary hOB and HOS, alkaline phosphatase activity decreased at the osteoblast proliferation stage, whereas it subsequently increased at the matrix maturation stage. ER beta mRNA was strongly expressed in HOS on day 15 and remained at high levels of transcription through to day 25 (matrix maturation phase), whereas ERalpha mRNA was barely detectable during osteoblast differentiation. In hOB, transcription of ERalpha mRNA was much stronger than that of ERbeta mRNA. CONCLUSION: The presence of ERalpha and ERbeta mRNA in osteoblasts supports the involvement of estrogen in human bone formation. The developmental expression of alkaline phosphatase was not correlated to ER mRNA expression during osteoblast differentiation. ER isoforms may have different functions or interact with each other during osteoblast differentiation. Since the expression of ER isoforms is different between postmenopausal women and osteosarcoma cell lines, characteristics of osteosarcoma cell lines may not be suitable as a model for the evaluation of estrogen effects on postmenopausal osteoporosis.

Aged↗
PubMed1998

Low-grade intraosseous osteosarcoma of the jaws.

Two cases of low-grade intraosseous osteosarcomas are reported, bringing the total number of such osteosarcomas in the jawbones documented in recent literature to six. Our first case involved the maxilla of a 69-year-old man and the second involved the mandible of an 18-year-old girl. In clinical and microscopic appearance, these neoplasms resemble benign proliferations in many respects. Subtle differences include cortical bone destruction, soft tissue infiltration, irregular bone production with foci of abundant osteoid, and mild cellular atypia. Complete removal at the first attempt is of paramount importance, inasmuch as a significant percentage of these neoplasms recur as high-grade osteosarcomas if they are inadequately treated.

Adolescent↗
PubMed2003

High-grade maxillofacial osteosarcoma: evolving strategies for a curable cancer.

Maxillofacial osteosarcoma is a rare tumour. Curative treatment strategies have evolved to include chemotherapy in addition to definitive surgical resection. To review and report our experience in eight patients with maxillofacial osteosarcomas, we retrospectively reviewed eight patients with high-grade maxillofacial osteosarcoma seen over the last decade at our institution. Our results suggest that a combined surgical and chemotherapy approach provides excellent local disease control and high cure rates.

Adolescent↗
PubMed2004

Impact of national health insurance on the survival rate of patients with osteosarcoma in Taiwan: review of 74 patients.

The 2-year survival rate for high-grade osteosarcoma was 46.9% before the introduction of National Health Insurance (NHI) in Taiwan on March 1, 1995, but increased to 73.8% after the implementation of NHI. The 5-year survival rate also increased, from 37.5% to 63.6%. Between May 1990 and May 2001, 74 patients with high-grade osteosarcoma were treated at our hospital. Median age was 17 years (range, 7-63 years). Inadequate surgical margins, poor histologic response to chemotherapy, advanced stage of disease, and incomplete treatment were strongly associated with poor prognosis. Before NHI, 10 patients had incomplete treatment, mainly because of unaffordable medical fees. After NHI, only three patients had incomplete treatment, due to personal reasons. Patient survival improved dramatically with advances in multiagent chemotherapy, but it was the NHI that enabled patients to complete expensive treatment courses, including preoperative neoadjuvant chemotherapy, limb-salvage surgery, and postoperative adjuvant chemotherapy. The NHI also improved the accessibility of medical care, with more patients presenting in the early stages of disease and, as a result, it not only improved survival rate but also increased the number of patients undergoing limb-salvage surgery. We concluded that the NHI significantly improved the survival rate for patients with osteosarcoma in Taiwan.

Adolescent↗
PubMed2005

Orbital metastatic osteosarcoma.

A 15-year-old girl with right tibial osteosarcoma, diagnosed 22 months previously, developed right orbital and skull base metastases, with symptoms including painful protrusion of the right eyeball and severe visual impairment. She underwent embolization of the metastatic tumor, local irradiation, and chemotherapy followed by intralesional resection of the mass because extensive involvement of the skull base precluded complete surgical resection. The best corrected visual acuity in her right eye initially decreased to 20/200, then dropped to no light perception after embolization, and then improved to counting fingers at 50 cm after radiotherapy. The symptoms of pain and proptosis subsided completely. After 24 months of follow-up from the presentation of orbital metastasis, the patient's right-eye vision remained unchanged. The surgical specimen revealed a necrotic tumor similar to osteosarcoma. In conclusion, orbital metastasis of osteosarcoma is rare, but may lead to severe visual impairment. Combined radiotherapy, chemotherapy and surgery can partially relieve symptoms, but cannot completely eradicate the tumors.

Adolescent↗
PubMed2005

Allograft arthrodesis of the knee in high-grade osteosarcoma.

BACKGROUND: A retrospective cohort study was conducted to evaluate the outcomes of massive allograft arthrodesis in the management of high-grade osteosarcoma around the knee. METHODS: The results of 19 patients with high-grade osteosarcoma around the knee, which was treated by wide resection and reconstruction using allograft arthrodesis, were evaluated for a mean length of 7.3 years (range, 3-13 years). The mean age at the time of surgery was 13.3 years (range, 6-27 years). According to the Musculoskeletal Tumor Society staging system, 17 patients were stage IIB and 2 were stage IIIB at presentation. Evaluations were based on the oncologic results, non-oncologic results and complications. Functional evaluation was performed with the Enneking functional evaluation form. RESULTS: Four patients (21.1%) died of their disease; 3 (15.8%) are alive with disease; and 12 (63.2%) are free of disease. Four patients (21.1%) had local recurrence of their tumor at a mean of 23 months postoperatively (range, 9-44 months). The mean time to union of the metaphyseal junction was 24.7 weeks (range, 16-30 weeks) and the diaphyseal junction was 47 weeks (range, 24-78 weeks). The overall complication rate was 31.6%, including 2 (10.5%) infections, 3 (15.8%) allograft fractures, and 1 (5.3%) nonunion. Our mean final functional result was 65%. CONCLUSION: Due to the high rate of complications in this study, we conclude that allograft arthrodesis should be left as a salvage or "back-up" reconstructive procedure after resection of osteosarcoma around the knee, unless there are special indications for this procedure. We found allograft fracture to be the most common complication.

Adolescent↗
PubMed2006

Comparison between F-18-FDG positron emission tomography and histology for the assessment of tumor necrosis rates in primary osteosarcoma.

BACKGROUND: The purpose of this prospective study was to identify if F-18-fluorodeoxy-D-glucose positron emission tomography (F-18-FDG PET) was a reliable noninvasive surrogate of histologic response in determining the efficacy of neoadjuvant chemotherapy before surgical resection in primary osteosarcoma. METHODS: Between January 2003 and December 2003, 10 patients with primary osteosarcomas were examined using F-18-FDG PET before neoadjuvant chemotherapy and surgery. The mean age at the time of first intervention was 19 years (range, 4-47 years). Positive prognostic significance was defined as more than 90% tumor necrosis response following neoadjuvant chemotherapy. The parameters of FDG uptake were correlated with histologic findings. The intraclass correlation coefficient was used to validate the tumor necrosis rates determined by PET and histology. RESULTS: The tumor necrosis rate determined by PET was comparable with that determined histologically. The mean standardized uptake value before and following neoadjuvant chemotherapy were 8.2 and 4.4, respectively. The average tumor necrosis rate determined by PET was 22%. However, the mean tumor necrosis rate determined histologically was 54.5%. According to the intraclass correlation coefficient models, the intraclass correlation coefficient equaled O. The relationship of tumor necrosis rates determined by F-18-FDG PET and histology seems to be statistically insignificant. CONCLUSION: In this preliminary study, FDG PET did not seem to be a promising tool for evaluating the response of primary osteosarcoma to neoadjuvant chemotherapy.

Adolescent↗