Osteogenic Sarcoma (osteosarcoma) is a bone forming cancer. It is the most frequent type of bone tumour and is most common between the ages of 15 to 25. Over 90% of tumours are located in the metaphysis (the growing ends of the bone), the most common sites are the bones around the knee which account for 80% of cases. Osteosarcomas vary greatly in radiological and pathological features and therefore needs careful diagnosis to differentiate this from other bone tumours. Most are high grade intramedullary osteosarcomas, about 5% are low grade lesions, some are secondary osteosarcomas (for example those caused by radiation therapy).
Figure 1. Radiograph showing an osteolytic and osteoblastic intra-medullary tumor characteristic of osteosarcoma. From Layfield J et al. Clin Med Pathol. 2008; 1: 55-59. Available under a Creative Commons CC-BY-3.0 license.
NHS Choices NHS Choices information is quality assured by experts and content is reviewed at least every 2 years. Further info. Overview of promary bone cancers in general, though does include some specific information about Osteosarcoma, Ewing's Sarcoma, Chondrosarcoma and Spindle cell sarcoma. Ewing's SarcomaEwing's Sarcoma
Information is reviewed by a panel of scientific and clinical experts, patients, parents/ carers, Further info. BCRT became a registered the charity in 2006 and raises funds for research into primary bone cancer, and provides information and support for patients and their families. The Website includes information booklets, personal stories and a section for teenagers. Bone CancersEwing's SarcomaEwing's Sarcoma
Bone Cancer Research Trust Information is reviewed by a panel of scientific and clinical experts, patients, parents/ carers, Further info. Overview of Osteosarcoma and the different types of the disease.
Mayo Clinic Dr. Carola Arndt discusses osteosarcoma which is one of the most common malignant tumors of bone in teenagers and young adults. She discusses diagnosis, evaluation, and treatment of osteosarcoma. Also mentions the Children's Oncology group and EURAMOS study. Mentions the multi-disciplinary approach at Mayo Clinic.
Founded in 2003 the initiative aims improve the quality of life for people dealing with sarcomas around the world, raising awareness and research funds. It has an international panel of medical experts. Ewing's SarcomaSoft Tissue SarcomasEwing's Sarcoma
PubMed Central search for free-access publications about Osteosarcoma MeSH term: Osteosarcoma US National Library of Medicine PubMed has over 22 million citations for biomedical literature from MEDLINE, life science journals, and online books. Constantly updated.
A website by orthopedic surgeon Dr. Henry DeGroot, with contributions from numerous clinical colleagues. It includes numerous case studies, including radiology and pathology images, and information covering a comprehensive range of bone tumours. Bone CancersEwing's SarcomaEwing's Sarcoma
This list of publications is regularly updated (Source: PubMed).
Incesu Z, Hatipoğlu I, Sivas H, et al. Effects of fibronectin and type IV collagen on osteosarcoma cell apoptosis. Indian J Exp Biol. 2013; 51(10):789-96 [PubMed] Related Publications
The aims of this study are the investigation of the effects of fibronectin and type IV collagen extracellular matrix proteins and the role of caspase-3 and -9 on cis-platin induced U2-OS apoptosis were studied. First the cytotoxic effects of cis-platin on cell system were investigated by colorimetric method and than morphological and ELISA analysis were used for determination of cell apoptosis when induced with cis-platin. In addition, after adhering the cells to fibronection or type IV collagen proteins, the apoptotic rate and the effects of caspase-3 and -9 were also investigated by ELISA in presence of specific inhibitors. U2-OS cells showed 20% cytotoxicity after treatment with 2.4 microM of cis-platin for 48 h. Morphological and the numerical data showed that cis-platin was able to induced apoptosis on cells as a dose-dependent manner. Caspase-3 and -9 inhibitors inhibited cis-platin-induced apoptosis in U2-OS cells, respectively. The binding of cells to 10 microg/mL of fibronectin but not type IV collagen enhanced the apoptosis about 2.5 fold that effects inhibited with caspase-3 inhibitor. The caspase-3 and -9 are involved in the apoptotic signals induced by cis-platin in U2-OS. The binding to fibronectin, but not type IV collagen enhanced the apoptotic response of U2-OS and fibronectin-dependent apoptosis was activated by caspase-3. These finding might be useful for patients to fight against osteosarcoma.
Tsagaraki I, Phenekos C, Tsilibary E, Tzinia A Calcitonin-induced NF-κB activation up-regulates fibronectin expression in MG63 osteosarcoma cells. Anticancer Res. 2013; 33(11):4901-6 [PubMed] Related Publications
Salmon calcitonin has been used extensively as a therapeutic tool in the regulation of bone remodeling. However, there is a growing body of evidence indicating that the calcitonin peptides are involved in regulation of cell growth, differentiation, survival and tissue development. In the present study, we investigated the effect of calcitonin in cell matrix interactions in MG63 cell line. Our results demonstrated that calcitonin increases cell growth of MG63 osteosarcoma cells in parallel with serine/threonine protein kinase B (AKT/PKB) activation. Moreover, calcitonin induced up-regulation of fibronectin expression in a nuclear factor-kappa B (NF-κB)-dependent manner, accompanied by enhanced enzymatic activity of matrix metalloproteinase-9 (MMP-9) and increased expression of tissue inhibitors of MMP-1 and -2. MMP-9 stimulation with calcitonin was accompanied by an increase in protein expression of the α5β1 integrin receptor. To our knowledge, our results demonstrate, for the first time, that calcitonin is a potent inducer of fibronectin, an extacellular matrix component that is suggested to have a pro-oncogenic and healing effect, in a NF-κB-dependent manner.
Lim JB, Sharma H, MacDuff E, Reece AT Primary osteosarcoma of the spine: a review of 10 cases. Acta Orthop Belg. 2013; 79(4):457-62 [PubMed] Related Publications
The authors describe 10 cases of osteosarcoma of the spine treated between January 1951 and December 2010, and obtained from the Tumour Registry of their hospital. The mean age at presentation was 38.8 years (range: 16-73 years); the mean duration of symptoms was 5.1 months (range: 3 weeks-1 year). Pain was the commonest complaint (9 patients), followed by neurological compromise (6 patients). The thoracic spine and male gender were predominant. Seven patients underwent marginal resection, 3 underwent intralesional resection. All, except one, had adjuvant chemotherapy and radiotherapy, pre- and/or postoperatively. This rare sarcoma has a dismal prognosis : the median survival period was only 23 years. The 1-year, 3-year and 5-year survival rates were 80%, 40% and 20%. Astonishingly, marginal resection (7 cases) did not lead to a longer survival than intralesional resection (3 cases): respectively 30 months and 42 months. Quite logically, local recurrence in 6 patients was linked to a survival of only 36 months, while the other 4 patients survived 52 months. Age below 40 was a positive factor, but not significantly. All patients had a reasonable quality of life with outcomes consistent with the available literature. Recent literature stresses that there is a trend toward improved survival with en bloc resection.
Tavanti E, Sero V, Vella S, et al. Preclinical validation of Aurora kinases-targeting drugs in osteosarcoma. Br J Cancer. 2013; 109(10):2607-18 [PubMed] Article available free on PMC after 12/11/2014 Related Publications
BACKGROUND: Aurora kinases are key regulators of cell cycle and represent new promising therapeutic targets in several human tumours. METHODS: Biological relevance of Aurora kinase-A and -B was assessed on osteosarcoma clinical samples and by silencing these genes with specific siRNA in three human osteosarcoma cell lines. In vitro efficacy of two Aurora kinases-targeting drugs (VX-680 and ZM447439) was evaluated on a panel of four drug-sensitive and six drug-resistant human osteosarcoma cell lines. RESULTS: Human osteosarcoma cell lines proved to be highly sensitive to both drugs. A decreased drug sensitivity was observed in doxorubicin-resistant cell lines, most probably related to ABCB1/MDR1 overexpression. Both drugs variably induced hyperploidy and apoptosis in the majority of cell lines. VX-680 also reduced in vitro cell motility and soft-agar cloning efficiency. Drug association experiments showed that VX-680 positively interacts with all conventional drugs used in osteosarcoma chemotherapy, overcoming the cross-resistance observed in the single-drug treatments. CONCLUSION: Aurora kinase-A and -B represent new candidate therapeutic targets for osteosarcoma. In vitro analysis of the Aurora kinases inhibitors VX-680 and ZM447439 indicated in VX-680 a new promising drug of potential clinical usefulness in association with conventional osteosarcoma chemotherapeutic agents.
Giang AH, Raymond T, Brookes P, et al. Mitochondrial dysfunction and permeability transition in osteosarcoma cells showing the Warburg effect. J Biol Chem. 2013; 288(46):33303-11 [PubMed] Article available free on PMC after 15/11/2014 Related Publications
Metabolic reprogramming in cancer is manifested by persistent aerobic glycolysis and suppression of mitochondrial function and is known as the Warburg effect. The Warburg effect contributes to cancer progression and is considered to be a promising therapeutic target. Understanding the mechanisms used by cancer cells to suppress their mitochondria may lead to development of new approaches to reverse metabolic reprogramming. We have evaluated mitochondrial function and morphology in poorly respiring LM7 and 143B osteosarcoma (OS) cell lines showing the Warburg effect in comparison with actively respiring Saos2 and HOS OS cells and noncancerous osteoblastic hFOB cells. In LM7 and 143B cells, we detected markers of the mitochondrial permeability transition (MPT), such as mitochondrial swelling, depolarization, and membrane permeabilization. In addition, we detected mitochondrial swelling in human OS xenografts in mice and archival human OS specimens using electron microscopy. The MPT inhibitor sanglifehrin A reversed MPT markers and increased respiration in LM7 and 143B cells. Our data suggest that the MPT may play a role in suppression of mitochondrial function, contributing to the Warburg effect in cancer.
Lauvrak SU, Munthe E, Kresse SH, et al. Functional characterisation of osteosarcoma cell lines and identification of mRNAs and miRNAs associated with aggressive cancer phenotypes. Br J Cancer. 2013; 109(8):2228-36 [PubMed] Article available free on PMC after 15/10/2014 Related Publications
BACKGROUND: Osteosarcoma is the most common primary malignant bone tumour, predominantly affecting children and adolescents. Cancer cell line models are required to understand the underlying mechanisms of tumour progression and for preclinical investigations. METHODS: To identify cell lines that are well suited for studies of critical cancer-related phenotypes, such as tumour initiation, growth and metastasis, we have evaluated 22 osteosarcoma cell lines for in vivo tumorigenicity, in vitro colony-forming ability, invasive/migratory potential and proliferation capacity. Importantly, we have also identified mRNA and microRNA (miRNA) gene expression patterns associated with these phenotypes by expression profiling. RESULTS: The cell lines exhibited a wide range of cancer-related phenotypes, from rather indolent to very aggressive. Several mRNAs were differentially expressed in highly aggressive osteosarcoma cell lines compared with non-aggressive cell lines, including RUNX2, several S100 genes, collagen genes and genes encoding proteins involved in growth factor binding, cell adhesion and extracellular matrix remodelling. Most notably, four genes-COL1A2, KYNU, ACTG2 and NPPB-were differentially expressed in high and non-aggressive cell lines for all the cancer-related phenotypes investigated, suggesting that they might have important roles in the process of osteosarcoma tumorigenesis. At the miRNA level, miR-199b-5p and mir-100-3p were downregulated in the highly aggressive cell lines, whereas miR-155-5p, miR-135b-5p and miR-146a-5p were upregulated. miR-135b-5p and miR-146a-5p were further predicted to be linked to the metastatic capacity of the disease. INTERPRETATION: The detailed characterisation of cell line phenotypes will support the selection of models to use for specific preclinical investigations. The differentially expressed mRNAs and miRNAs identified in this study may represent good candidates for future therapeutic targets. To our knowledge, this is the first time that expression profiles are associated with functional characteristics of osteosarcoma cell lines.
Posthumadeboer J, Piersma SR, Pham TV, et al. Surface proteomic analysis of osteosarcoma identifies EPHA2 as receptor for targeted drug delivery. Br J Cancer. 2013; 109(8):2142-54 [PubMed] Article available free on PMC after 15/10/2014 Related Publications
BACKGROUND: Osteosarcoma (OS) is the most common bone tumour in children and adolescents. Despite aggressive therapy regimens, treatment outcomes are unsatisfactory. Targeted delivery of drugs can provide higher effective doses at the site of the tumour, ultimately improving the efficacy of existing therapy. Identification of suitable receptors for drug targeting is an essential step in the design of targeted therapy for OS. METHODS: We conducted a comparative analysis of the surface proteome of human OS cells and osteoblasts using cell surface biotinylation combined with nano-liquid chromatography - tandem mass spectrometry-based proteomics to identify surface proteins specifically upregulated on OS cells. This approach generated an extensive data set from which we selected a candidate to study for its suitability as receptor for targeted treatment delivery to OS. First, surface expression of the ephrin type-A receptor 2 (EPHA2) receptor was confirmed using FACS analysis. Ephrin type-A receptor 2 expression in human tumour tissue was tested using immunohistochemistry. Receptor targeting and internalisation studies were conducted to assess intracellular uptake of targeted modalities via EPHA2. Finally, tissue micro arrays containing cores of human OS tissue were stained using immunohistochemistry and EPHA2 staining was correlated to clinical outcome measures. RESULTS: Using mass spectrometry, a total of 2841 proteins were identified of which 156 were surface proteins significantly upregulated on OS cells compared with human primary osteoblasts. Ephrin type-A receptor 2 was highly upregulated and the most abundant surface protein on OS cells. In addition, EPHA2 was expressed in a vast majority of human OS samples. Ephrin type-A receptor 2 effectively mediates internalisation of targeted adenoviral vectors into OS cells. Patients with EPHA2-positive tumours showed a trend toward inferior overall survival. CONCLUSION: The results presented here suggest that the EPHA2 receptor can be considered an attractive candidate receptor for targeted delivery of therapeutics to OS.
Botchu R, Douis H, Davies AM, et al. Post-traumatic heterotopic ossification of distal tibiofibular syndesmosis mimicking a surface osteosarcoma. Clin Radiol. 2013; 68(12):e676-9 [PubMed] Related Publications
AIM: To present the imaging features of post-traumatic heterotopic ossification (HO) of the distal tibiofibular syndesmosis initially suspected to be a surface osteosarcoma. MATERIALS AND METHODS: A retrospective review was conducted of the presenting complaint and imaging features of patients with a final diagnosis of HO referred over an 8 year period to a specialist orthopaedic oncology centre. RESULTS: Five patients with HO were identified. All were adult males with an age range of 19-41 years. There was a history of prior ankle trauma in all cases but the significance was not recognized at the time of referral to the specialist centre. There was radiographic evidence of HO arising from the inner aspects of the distal tibia and fibula approximately 3 cm proximal to the ankle joint. The HO was "kissing" in two cases and partially fused (synostosis) in two. The HO in the fifth case was arising on the inner fibular cortex alone. Magnetic resonance imaging (MRI), available in four cases, showed predominantly low signal intensity due to the dense bone formation. CONCLUSION: The history of prior ankle trauma with ossification arising from the inner aspects of both the distal tibia and fibula is typical of post-traumatic HO and distinguish this benign condition from the rare surface osteosarcoma at this site.
Tome Y, Kimura H, Maehara H, et al. High lung-metastatic variant of human osteosarcoma cells, selected by passage of lung metastasis in nude mice, is associated with increased expression of α(v)β(3) integrin. Anticancer Res. 2013; 33(9):3623-7 [PubMed] Related Publications
Altered expression of αvβ3 integrin is associated with tumor progression and metastasis in several types of cancer, including metastatic osteosarcoma. In this study, we demonstrate that in vivo passaging of lung metastasis in nude mice can generate an aggressive variant of human osteosarcoma cells. Experimental metastases were established by injecting 143B human osteosarcoma cells, expressing green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in the cytoplasm, in the tail vein of nude mice. Lung metastases were harvested under fluorescence microscopy from nude mice to establish cell lines which were then injected via the tail vein of additional nude mice. This procedure was repeated for four passages in order to isolate highly metastatic variant sublines. When the parental and metastatic variants were transplanted orthotopically into the tibia of nude mice, the 143B-LM4 variant had the highest metastatic rate, approximately 18-fold higher than the parent (p<0.01). αvβ3 integrin expression was increased approximately 5.6-fold in 143B-LM4 compared to parental cells (p<0.05). Thus, serial passage of lung metastases created a highly metastatic variant of human osteosarcoma cells which had increased expression of αvβ3 integrin, suggesting that αvβ3 integrin plays an essential role in osteosarcoma metastasis. With this highly metastatic variant overexpressing αvβ3 integrin, it will now be possible to further investigate the mechanism by which αvβ3 integrin facilitates metastasis.
Zhao Z, Wu MS, Zou C, et al. Downregulation of MCT1 inhibits tumor growth, metastasis and enhances chemotherapeutic efficacy in osteosarcoma through regulation of the NF-κB pathway. Cancer Lett. 2014; 342(1):150-8 [PubMed] Related Publications
Monocarboxylate transporter isoform 1 (MCT1) is an important member of the proton-linked MCT family and has been reported in an array of human cancer cell lines and primary human tumors. MCT1 expression is associated with developing a new therapeutic approach for cancer. In this study, we initially showed that MCT1 is expressed in a variety of human osteosarcoma cell lines. Moreover, we evaluated the therapeutic response of targeting MCT1 using shRNA or MCT1 inhibitor. Inhibiting MCT1 delayed tumor growth in vitro and in vivo, including in an orthotopic model of osteosarcoma. Targeting MCT1 greatly enhanced the sensitivity of human osteosarcoma cells to the chemotherapeutic drugs adriamycin (ADM). In addition, we observed that MCT1 knockdown significantly suppressed the metastatic activity of osteosarcoma, including wound healing, invasion and migration. Further mechanistic studies revealed that the antitumor effects of targeting MCT1 might be related to the NF-κB pathway. Immunochemistry assay showed that MCT1 was an independent positive prognostic marker in osteosarcoma patients. In conclusion, our data, for the first time, demonstrate that MCT1 inhibition has antitumor potential which is associated with the NF-κB pathway, and high MCT1 expression predicates poor overall survival in patients with osteosarcoma.
Liu T, Liu ZY, Zhang Q, Zhang XS Hemicortical resection and reconstruction using pasteurised autograft for parosteal osteosarcoma of the distal femur. Bone Joint J. 2013; 95-B(9):1275-9 [PubMed] Related Publications
The aim of this study was to assess a specific protocol for the treatment of patients with a parosteal osteosarcoma of the distal femur with limb salvage involving hemicortical resection and reconstruction using recycled pasteurised autograft and internal fixation. Between January 2000 and January 2010, 13 patients with a mean age of 26.5 years (17 to 39) underwent this procedure. All the tumours were staged according to Enneking's criteria: there were eight stage IA tumours and five stage IB tumours. The mean follow-up was 101.6 months (58 to 142), and mean post-operative Musculoskeletal Tumour Society functional score was 88.6% (80% to 100%) at the final follow-up. All the patients had achieved bony union; the mean time to union was 11.2 months (6 to 18). Local recurrence occurred in one patient 27 months post-operatively. No patient had a pulmonary metastasis. A hemicortical procedure for the treatment of a parosteal osteosarcoma is safe and effective. Precise pre-operative planning using MRI is essential in order to define the margins of resection. Although it is a technically demanding procedure, gratifying results make it worthwhile for selected patients.
Li X, Huang T, Jiang G, et al. Proteasome inhibitor MG132 enhances TRAIL-induced apoptosis and inhibits invasion of human osteosarcoma OS732 cells. Biochem Biophys Res Commun. 2013; 439(2):179-86 [PubMed] Related Publications
MG132 as a proteasome inhibitor could induce apoptosis in various cancer cells. This study aimed to discuss the effect of proteasome inhibitor MG132 on the TRAIL-induced apoptosis of human osteosarcoma OS732 cells. MG132 and TRAIL were applied on OS732 cells respectively or jointly. Cell survival rates, changes of cellular shape, cell apoptosis and cell invasion were analyzed, respectively, by 3-(4,5)-dimethylthiahiazo(-z-y1)-2,5-di-phenytetrazoliumromide (MTT) assay, inverted phase contrast microscope, flow cytometry, and transwell invasion chamber methods. The protein levels of DR5, caspase-3, caspase-8, p27(kip1) and MMP-9 were measured by Western blot analysis. The results indicated that combination of MG132 and TRAIL had the effect of up-regulating expression of DR5, caspase-3, caspase-8 and p27(kip1), down-regulating expression of MMP-9 and inducing apoptosis as well as suppressing the ability of invasion of OS732 cells. The survival rate of combined application of 10 μM MG132 and 100 ng/ml TRAIL on OS732 cells was significantly lower than that of the individual application (p<0.01). Changes of cellular shape and apoptotic rates also indicated the apoptosis-inducing effect of combined application was much stronger than that of individual application. Cell cycle analysis showed combination of MG132 and TRAIL mostly caused OS732 cells arrested at G2-M-phase. The invasion ability of OS732 cells was restrained significantly in the combined group compared with the individual group and control group.
Wang J, Nong L, Wei Y, et al. Association of interleukin-12 polymorphisms and serum IL-12p40 levels with osteosarcoma risk. DNA Cell Biol. 2013; 32(10):605-10 [PubMed] Related Publications
No previous studies reported the association of IL-12 polymorphisms with osteosarcoma. We aimed to investigate the association in a Chinese population. IL-12A rs568408, rs2243115, and IL-12B rs3212227 polymorphisms were evaluated in a case-control study of 106 osteosarcoma patients and 210 health controls by using polymerase chain reaction-restriction fragment length polymorphism. Serum IL-12p40 levels were measured by enzyme-linked immunosorbent assay. The serum IL-12p40 levels were significantly higher in controls than those in osteosarcoma patients (p<0.01). Genotypes of rs568408 GA and GA/AA, and rs3212227 CC and AC/CC were associated with the risk of osteosarcoma (rs568408 GA: odds ratios [OR]=1.86, 95% confidence intervals [CI]=1.11-3.12; GA/AA: OR=1.75, 95% CI=1.06-2.89, and rs3212227 CC: OR=2.70, 95% CI=1.38-5.28; CC/AC: OR=1.73, 95% CI=1.03-2.90). Moreover, rs3212227 CC/AC genotypes were significantly associated with decreased serum IL-12p40 levels in osteosarcoma patients compared to AA genotypes (p=0.035). Stratification analysis showed no associations between rs3212227 variant and the patients' gender, tumor location, and metastasis. Our data suggest that the serum IL-12p40 levels associate with the risk of osteosarcoma and are regulated by IL-12B rs3212227 polymorphism. The IL-12A rs568408 and IL-12B rs3212227 may confer the susceptibility to osteosarcoma risk.
Altaf S, Enders F, Jeavons E, et al. High-BMI at diagnosis is associated with inferior survival in patients with osteosarcoma: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2013; 60(12):2042-6 [PubMed] Related Publications
BACKGROUND: Body mass index (BMI), at diagnosis has been associated with lower survival and increased toxicity in cancer patients. We analyzed the effect of BMI at diagnosis on therapy related toxicities and outcome in pediatric osteosarcoma patients treated on Children's Oncology Group (COG) trial INT0133. PROCEDURES: All patients enrolled on COG-INT0133 with height, weight and toxicity information were eligible. BMI was expressed as age and gender specific percentiles using height and weight at diagnosis. Patients were classified into high, normal and low BMI groups. Logistic regression models were used to analyze toxicities; Kaplan-Meier curves were created to assess event free (EFS) and overall survival (OAS). RESULTS: Seven hundred and ten patients met eligibility criteria. BMI distribution was: 447 normal BMI, 74 low BMI, and 189 high BMI. Renal toxicity was higher in the high BMI group (OR = 2.7, 95% CI 1.2-6.4, P = = 0.01) only during one of the courses of therapy. Compared to the normal BMI group, patients with high BMI had significantly worse OAS at 5 years compared to those with normal BMI, 69.7% versus 80.5% (HR = 1.6, 95% CI 1.1-2.2, P = 0.005) and a trend towards worse event-free survival at 3 years 66.2% versus 75.5% (HR = 1.3 95% CI 0.9-1.8, P = 0.05). There was no difference in EFS or OAS in patients with low BMI compared to patients with normal BMI. CONCLUSIONS: High BMI at diagnosis is associated with worse OAS in patients with osteosarcoma. No clinically significant differences in toxicity were observed in the various BMI groups.
Byun BH, Kong CB, Park J, et al. Initial metabolic tumor volume measured by 18F-FDG PET/CT can predict the outcome of osteosarcoma of the extremities. J Nucl Med. 2013; 54(10):1725-32 [PubMed] Related Publications
UNLABELLED: We evaluated the ability of metabolic and volumetric parameters measured by pretreatment (18)F-FDG PET/CT to predict the survival of patients with osteosarcoma of the extremities. METHODS: The records of 83 patients with American Joint Committee on Cancer stage II extremity osteosarcoma treated with surgery and chemotherapy were retrospectively reviewed. Imaging parameters (maximum standardized uptake value, metabolic tumor volume [MTV], total lesion glycolysis, and tumor volume based on MR images) were measured before treatment, and histologic responses to neoadjuvant chemotherapy were assessed by examination of postsurgical specimens. Receiver-operating-characteristic curve analyses and the Cox proportional hazards model were used to analyze whether imaging and clinicopathologic parameters could predict metastasis-free survival. RESULTS: Of the imaging parameters, MTV at the fixed standardized uptake value threshold of 2.0 (MTV(2.0)) most accurately predicted metastasis by receiver-operating-characteristic curve analysis (area under the curve = 0.679, P = 0.011). By multivariate analysis, MTV(2.0) > 105 mL (relative risk, 3.93; 95% confidence interval, 1.55-9.92) and poor response to neoadjuvant chemotherapy (relative risk, 4.83; 95% confidence interval, 1.64-14.21) independently shortened metastasis-free survival (P = 0.004 for both parameters). The stratification of patients by the combined criteria of MTV(2.0) and histologic response predicted outcome in more detail. CONCLUSION: MTV is an independent predictor of metastasis in patients with osteosarcoma of the extremities. The combination of MTV and histologic response predicts survival more accurately than the chemotherapeutic response alone.
Abbo O, Pinnagoda K, Micol LA, et al. Osteosarcoma metastasis causing ileo-ileal intussusception. World J Surg Oncol. 2013; 11(1):188 [PubMed] Article available free on PMC after 15/10/2014 Related Publications
Osteosarcoma metastasis causing intussusception is a very rare entity, with a pejorative prognosis. Based on a case, we performed a literature review in order to better assess this situation. We conclude that, in patients with a history of osteosarcoma lung metastasis, echographic and/or computed tomography scan evidence of a small bowel obstruction with intussusception should lead to an open surgical procedure if the laparoscopic approach does not allow to accurately explore and resect the lesion, in order to prevent misdiagnosis and to avoid further delay in the management.
Ottaviani G, Robert RS, Huh WW, et al. Sociooccupational and physical outcomes more than 20 years after the diagnosis of osteosarcoma in children and adolescents: limb salvage versus amputation. Cancer. 2013; 119(20):3727-36 [PubMed] Article available free on PMC after 15/10/2014 Related Publications
BACKGROUND: To the best of the authors' knowledge, there has been relatively little research published to date regarding very long-term survivors of childhood and adolescent osteosarcoma. In the current study, the authors compared the very long-term survival outcomes of patients with osteosarcoma who were treated with either limb salvage procedures or amputation. METHODS: A total of 38 patients with osteosarcoma who survived ≥ 20 years from the time of diagnosis were divided into 2 groups according to whether they underwent amputation or limb salvage. Participants were asked to complete a questionnaire concerning their education, employment, annual income, marital status, health insurance, lifestyle, siblings, and all current and past health issues. RESULTS: Education, employment, marital status, and health insurance were not found to differ significantly between the 2 groups of survivors, who described themselves as being similar to their siblings. Eight percent of survivors underwent secondary amputation because of complications with an endoprosthesis. The cumulative incidence of second primary neoplasms was 13%, and this finding was significantly higher in females and in survivors who underwent radiotherapy and had a genetic predisposition. The second primary malignancies were breast cancer (ductal invasive carcinoma, ductal in situ carcinoma, and leiomyosarcoma), mediastinal leiomyosarcoma, and squamocellular carcinoma of the oral cavity and the uterine cervix. Amputees required more assistive walking support than survivors who received limb salvage treatment (P<.05, chi-square test). CONCLUSIONS: Despite the many challenges that osteosarcoma survivors face, patients who survived ≥ 20 years after their initial diagnosis reported having overall adjusted well to their physical limitations and were productive individuals.
Tome Y, Sugimoto N, Yano S, et al. Real-time imaging of αv integrin molecular dynamics in osteosarcoma cells in vitro and in vivo. Anticancer Res. 2013; 33(8):3021-5 [PubMed] Related Publications
αv Integrin is involved in various steps of cancer metastasis. In this report, we describe real-time imaging of αv integrin molecular dynamics in human 143B osteosarcoma cells in vitro and in vivo. We first generated osteosarcoma cells expressing αv integrin green fluorescent protein (GFP) by transfection of an αv integrin GFP fusion vector (pCMV6-AC-ITGAV-GFP) into 143B cells. Confocal laser-scanning microscopy demonstrated that αv integrin immunofluorescence staining co-localized with αv integrin-GFP fluorescence in 143B cells. When αv integrin-GFP-expressing 143B osteosarcoma cells were seeded on a dish coated with fibronectin, which is bound by αv integrin, punctate αv integrin-GFP was observed by confocal laser-scanning microscopy. When the 143B αv integrin-GFP cells were seeded onto uncoated plastic, αv integrin-GFP was diffuse within the cells. When αv integrin-GFP 143B osteosarcoma cells (1×10(6)) were orthotopically transplanted into the tibia of nude mice, the cells aligned along the collagen fibers within the tumor and had punctuate expression of αv integrin-GFP. In the orthotopic model, the invading osteosarcoma cells had punctate αv integrin-GFP in the muscle tissue at the primary tumor margin. These results show that αv integrin-GFP enables the imaging of the molecular dynamics of αv integrin in osteosarcoma cells in vitro and in vivo.
Bernardi Fdel C, Garcia JL, de Almeida MT, et al. Minimally invasive adenocarcinoma of the lung in a young patient treated for osteosarcoma. Pediatr Dev Pathol. 2013 Sep-Oct; 16(5):387-90 [PubMed] Related Publications
Although children with osteosarcoma have a higher incidence of a 2nd malignancy than the general population, its development in the lung is rare. The few reported cases belong to examples of carcinomas. Here we present the case of a 13-year-old boy with a primary pulmonary adenocarcinoma diagnosed 3 years after the osteosarcoma diagnosis and present a review of the literature.
Zhou X, Wei M, Wang W MicroRNA-340 suppresses osteosarcoma tumor growth and metastasis by directly targeting ROCK1. Biochem Biophys Res Commun. 2013; 437(4):653-8 [PubMed] Related Publications
MicroRNAs (miRNAs) play key roles in cancer development and progression. In the present study, we investigated the role of miR-340 in the progression and metastasis of osteosarcoma (OS). Our results showed that miR-340 was frequently downregulated in OS tumors and cell lines. Overexpression of miR-340 in OS cell lines significantly inhibited cell proliferation, migration, and invasion in vitro, and tumor growth and metastasis in a xenograft mouse model. ROCK1 was identified as a target of miR-340, and ectopic expression of miR-340 downregulated ROCK1 by direct binding to its 3' untranslated region. siRNA-mediated silencing of ROCK1 phenocopied the effects of miR-340 overexpression, whereas restoration of ROCK1 in miR-340-overexpressing OS cells reversed the suppressive effects of miR-340. Together, these findings indicate that miR-340 acts as a tumor suppressor and its downregulation in tumor tissues may contribute to the progression and metastasis of OS through a mechanism involving ROCK1, suggesting miR-340 as a potential new diagnostic and therapeutic target for the treatment of OS.
Thampi S, Matthay KK, Goldsby R, DuBois SG Adverse impact of regional lymph node involvement in osteosarcoma. Eur J Cancer. 2013; 49(16):3471-6 [PubMed] Related Publications
BACKGROUND: Metastatic dissemination in osteosarcoma occurs haematogenously, though regional lymph node involvement is rarely reported. We investigated incidence, patient characteristics and survival for patients with osteosarcoma and regional lymph node involvement at diagnosis. METHODS: We identified 2748 cases of high-grade osteosarcoma with available information regarding regional lymph node involvement in the Surveillance Epidemiology and End Results database from 1973 to 2009. Demographics were compared using chi-squared tests or t-tests. Overall survival was estimated using Kaplan-Meier method and compared with log-rank tests. Multivariate analysis of overall survival was performed using Cox proportional hazards methods. RESULTS: There were 74 patients (2.7%) with regional lymph node involvement at diagnosis of whom 19 (0.7%) were pathologically confirmed. Patients with regional node involvement were more likely to have extraskeletal tumours, distant metastases, tumours arising outside the lower extremity (p<0.0001 for all comparisons) and larger tumours (p=0.033). Five-year overall survival in those with and without regional node involvement was 10.9% (95% confidence interval (CI) 4.6-20.4) and 54.3% (95% CI 52.2-56.4; p<0.0001). In multivariate analysis, regional node involvement remained predictive of inferior survival after controlling for differences in metastatic status, age, tumour site and extraskeletal origin (hazard ratio 2.05, 95% CI 1.57-2.67; p<0.0001). Similar survival results were found when the analysis was restricted to patients with pathologically confirmed positive or negative regional lymph nodes. CONCLUSION: This analysis confirms that regional node involvement is a significant adverse prognostic factor that is independent of metastatic status, extraskeletal origin, age and tumour site.
Guo J, Cui Q, Jiang W, et al. Research on DNA methylation of human osteosarcoma cell MGMT and its relationship with cell resistance to alkylating agents. Biochem Cell Biol. 2013; 91(4):209-13 [PubMed] Related Publications
The objective of this study was to explore the O(6)-methylguanine-DNA methyltransferase (MGMT) gene methylation status and its protein expression, as well as the effects of demethylating agent 5-Aza-2'-deoxycytidine (5-Aza-CdR) on MGMT gene expression and its resistance to alkylating agents, and to elucidate MGMT expression mechanism and significance in osteosarcoma. The human osteosarcoma cell lines Saos-2 and MG-63 were collected and treated with 5-Aza-CdR for 6 days. The cells not treated with 5-Aza-CdR were set as a negative control. The genomic DNA was extracted from the Saos-2 and MG-63 cells using methylation-specific PCR to detect the promoter CpG island methylation status of the MGMT gene. Cell sensitivity to alkylating agents before and after drug administration was detected by the MTT method. The variation in MGMT gene mRNA and protein was detected by reverse transcription PCR (RT-PCR) and Western blotting. The MGMT promoter gene of normal Saos-2 cells was methylated, with reduced MGMT mRNA and protein expression; the MGMT mRNA and protein expression of Saos-2 cells treated with 5-Aza-CdR was obviously enhanced, and its sensitivity to alkylating agents was reversed. Meanwhile, with promoter CpG island unmethylation of the MGMT gene, MGMT protein was expressed in the normal MG-63 cells and the MG-63 cells treated with 5-Aza-CdR, and both showed resistance to alkylating agents. The methylation status of the MGMT gene promoter in human osteosarcoma cells reflected the cells' ability to induce MGMT protein expression and can be used as a molecular marker to project the sensitivity of cancer tissues to alkylating agent drugs.
Jiao G, Ren T, Lu Q, et al. Prognostic significance of cyclooxygenase-2 in osteosarcoma: a meta-analysis. Tumour Biol. 2013; 34(5):2489-95 [PubMed] Related Publications
Published studies researching the prognostic significance of cyclooxygenase-2 (COX-2) expression in patients with osteosarcoma are inconclusive and heterogeneous. We conducted a meta-analysis to assess its prognostic value more precisely. The pooled odds ratios (ORs) or hazard ratios (HRs) with corresponding 95 % confidence intervals (CIs) were calculated to evaluate the effects. Fourteen studies with 735 osteosarcoma patients were included to estimate the relationship between COX-2 and metastasis of tumor, clinical stage, and 3-year overall survival. High expressions of COX-2 predicted neoplasm metastasis (OR = 1.891, 95 % CI 1.276-2.803, P = 0.002), advanced clinical stage (OR = 1.801, 95 % CI 1.257-2.581, P = 0.001). In addition, high COX-2 expression tended to be associated with a poor 3-year survival (HR = 1.741, 95 % CI 0.762-3.979, P = 0.188), but the difference was not significant. Therefore, this meta-analysis demonstrated that high COX-2 expression might be an unfavorable prognostic effect in osteosarcoma.
Zhang Y, Hu H, Song L, et al. Epirubicin-mediated expression of miR-302b is involved in osteosarcoma apoptosis and cell cycle regulation. Toxicol Lett. 2013; 222(1):1-9 [PubMed] Related Publications
Epirubicin is widely used in osteosarcoma chemotherapy. Growing evidence indicates that the microRNA (miRNA) expression levels which are induced by chemotherapeutic agents play an important role in osteosarcoma development and progression. In this study we investigate the alterations of miRNA expression in the osteosarcoma cells after epirubicin treatment and whether miRNAs can enhance its anti-osteosarcoma effect. After epirubicin exposure, microarray shows 40 miRNAs are differentially expressed in osteosarcoma cells including 24 down-regulated miRNAs. Notably, miR-302b, which is stably low-expressed in osteosarcoma, could be induced by the epirubicin. Furthermore, we find that miR-302b can inhibit the osteosarcoma cell proliferation, promote cell apoptosis and cell cycle arrest MiR-302b can activate caspase-3 and regulate the Akt/pAkt, Bcl-2, Bim expression to increase the cell apoptosis. Meanwhile, miR-302b also attenuates cyclin D1 and CDKs expression to induce cell cycle arrest. Therefore, our results suggest miR-302b can play an essential role in osteosarcoma treatment as a potential tumor suppressor.
Le Guellec S, Moyal EC, Filleron T, et al. The β5/focal adhesion kinase/glycogen synthase kinase 3β integrin pathway in high-grade osteosarcoma: a protein expression profile predictive of response to neoadjuvant chemotherapy. Hum Pathol. 2013; 44(10):2149-58 [PubMed] Related Publications
To date, chemosensitivity to neoadjuvant chemotherapy of patients with high-grade osteosarcoma is evaluated on surgical resection by evaluation of the percentage of necrotic cells. As yet, no predictive profile of response to chemotherapy has been used in clinical practice. Because we have previously shown that the integrin pathway controls genotoxic-induced cell death and hypoxia, we hypothesized that in primary biopsies, expression of proteins involved in this pathway could be associated with sensitivity to neoadjuvant chemotherapy in high-grade osteosarcoma. We studied β1, β3, and β5 integrin expression and integrin-linked kinase, focal adhesion kinase (FAK), glycogen synthase kinase 3β (GSK3β), Rho B, angiopoietin-2, β-catenin, and ezrin expression by immunohistochemistry in 36 biopsies of osteosarcomas obtained before treatment. All patients received a chemotherapy regimen in the neoadjuvant setting. An immunoreactive score was assessed, combining the percentage of positive tumor cells and staining intensity. We evaluated the correlation of the biomarkers with response to chemotherapy, metastasis-free survival, and overall survival. A combination of 3 biomarkers (β5 integrin, FAK, and GSK3β) discriminated good and poor responders to chemotherapy, with the highest area under the curve (89.9%; 95% confidence interval, 77.4-1.00) and a diagnostic accuracy of 90.3%. Moreover, high expression of ezrin was associated with an increased risk of metastasis (hazard ratio, 3.93; 95% confidence interval, 1.19-12.9; P = .024). We report a protein expression profile in high-grade osteosarcoma associating β5 integrin, FAK, and GSK3β that significantly correlates with poor response to neoadjuvant chemotherapy. This biomarker profile could help select patients for whom an alternative protocol using inhibitors of this pathway can be proposed.
Salinas-Souza C, De Oliveira R, Alves MT, et al. The metastatic behavior of osteosarcoma by gene expression and cytogenetic analyses. Hum Pathol. 2013; 44(10):2188-98 [PubMed] Related Publications
Osteosarcoma is a malignant bone tumor with high metastatic potential. Metastasis at diagnosis is the most significant prognostic factor in predicting the clinical outcome of osteosarcoma. We compared the gene expression of metastases that were present at the time of initial diagnosis to those developed later in the course of the disease. We used quantitative real-time polymerase chain reaction to evaluate the gene expression of MDM2, CXCR4, RANKL, RB1, and OSTERIX in 98 samples of osteosarcoma taken from 47 patients (74 metastases and 24 primary tumors) and 30 nonmalignant lung tissues surrounding osteosarcoma metastases. In addition, we investigated the copy number changes of RB1 and MDM2 genes in 12 primary cultures of pulmonary metastases of osteosarcoma, using interphase fluorescence in situ hybridization. Metastases from metastatic patients at diagnosis were characterized by low expression of RB1 and RANKL (P = .0009 and P = .0109, respectively) and overexpression of CXCR4 and MDM2 (P = .0389 and P = .0325, respectively). The loss of RANKL and gain of CXCR4 could also be detected in the primary tumors of metastatic patients at diagnosis (P = .0121 and P = .0264, respectively). Thus, some early genetic events such as the loss of RANKL and the gain of CXCR4 expressions probably facilitate the metastatic progression concomitant with the primary tumor establishment, supporting the role of the CXCR4 receptor in directing osteosarcoma metastases to the lung. On the other hand, late events such as the loss of RB1 and gain of MDM2, crucial regulators of cell cycle, appear to be related to the final mechanisms contributing to the metastatic establishment of osteosarcoma.
Rathmanner N, Haigl B, Vanas V, et al. Sprouty2 but not Sprouty4 is a potent inhibitor of cell proliferation and migration of osteosarcoma cells. FEBS Lett. 2013; 587(16):2597-605 [PubMed] Related Publications
As negative regulators of receptor tyrosine kinase-mediated signalling, Sprouty proteins fulfil important roles during carcinogenesis. In this report, we demonstrate that Sprouty2 protein expression inhibits cell proliferation and migration in osteosarcoma-derived cells. Although earlier reports describe a tumour-promoting function, these results indicate that Sprouty proteins also have the potential to function as tumour suppressors in sarcoma. In contrast to Sprouty2, Sprouty4 expression failed to interfere with proliferation and migration of the osteosarcoma-derived cells, possibly due to a less pronounced interference with mitogen-activated protein kinase activity. Sequences within the NH2-terminus are responsible for the specific inhibitory function of Sprouty2 protein.
Li X, Huang T, Jiang G, et al. Synergistic apoptotic effect of crocin and cisplatin on osteosarcoma cells via caspase induced apoptosis. Toxicol Lett. 2013; 221(3):197-204 [PubMed] Related Publications
Crocin is well-known traditional Chinese medicine which is extracted from saffron. However, its role in osteosarcoma has not been well understood. Therefore, we used crocin and cisplatin individually or jointly on MG63 and OS732 cells so as to explore whether crocin could induce cellular apoptosis and suppress the ability of invasion of osteosarcoma cells. Cell survival rates, changes of cellular shape, cell apoptosis and cell invasion were analyzed, respectively, by 3-(4,5)-dimethylthiahiazo (-z-y1)-2,5-di- phenytetrazoliumromide (MTT) assay, inverted phase contrast microscope and fluorescence microscope, ﬂow cytometry, and Transwell invasion chamber methods. The expressions of caspase-3 and caspase-8 were detected by Western blot. The survival rate of combined application was significantly lower than that of the individual application. Apoptosis-inducing effect of combined application was much stronger than that of individual application. The invasion ability of MG63 and OS732 cells was restrained significantly in the combined group compared with the individual group and control group. Combined group has the effect of up-regulating the expressions of cleaved-caspase-3 and caspase-8. The results suggested that combination of crocin and cisplatin has a strong killing effect on osteosarcoma cells and suppresses the ability of invasion of MG63 and OS732 cells which might be related to up-regulate the expression of caspase-3 and caspase-8.
Kobys VL, Konovalenko VF, Repinа NV, et al. Treatment of large osteosarcoma in children: new approach. Exp Oncol. 2013; 35(2):105-8 [PubMed] Related Publications
AIM: To improve the treatment results of patients with locally advanced osteosarcoma with large volume using neoadjuvant chemotherapy (NACT) (ifosfamide at a dose of 18 g/ml) and planning of organ-conserving surgery by evaluating the state of tumor pseudocapsule. PATIENTS AND METHODS: A study group included 46 children aged from 7 to 18 years, mean age - 12 years. In 68% of the patients tumor volume was larger or significantly larger than 200 ml (from 27 to 2400 ml), mean tumor volume was 342 ml. All patients have been examined by X-ray radiography, CT, Doppler ultrasound. Convenient chemotherapy consisted of methotrexate at a dose of 12 g/ml, cisplatin (120 mg/ml) in combination with doxorubicin (75 mg/ml). If such chemotherapy was considered ineffective with the use of an algorithm for determination of chemotherapy efficacy, 2 cycles of chemotherapy with ifosfamide at a dose of 18 g/ml per course have been applied. At the stage of planning of organ-conserving surgery, the state of tumor pseudocapsule was analyzed. In 6 months post-operative chemotherapy was carried out with the use of methotrexate, cisplatin with doxorubicin, ifosfamide at the same doses. RESULTS: Myelotoxicity of ifosfamide treatment at a dose of 18 g/ml is comparable to that of to a course of doxorubicin + cisplatin: the depth of leucopenia was significantly higher (p < 0.05), the duration of agranulocytosis is similar after such therapies. In the study group, 69.6% patients have reached grade 3-4 pathomorphosis. Organ-conserving surgery was performed in 86.9% of the patients. Local tumor recurrence was registered in 15.2% patients of the study group. 5-year relapse-free survival was achieved in 62 ± 10% (p = 0.02), the overall 5-year survival - 76.5 ± 9% (p = 0.02). CONCLUSIONS: Introduction of ifosfamide at a dose of 18 g/ml in the treatment scheme of pediatric patients with locally advanced osteosarcoma along with individualization of pre-operative chemotherapy, pre-operative analysis of NACT efficacy and the state of tumor pseudocapsule during planning stage of organ-conserving surgery significantly improves efficacy of the therapy in patients with large tumor volume.
Miller BJ, Cram P, Lynch CF, Buckwalter JA Risk factors for metastatic disease at presentation with osteosarcoma: an analysis of the SEER database. J Bone Joint Surg Am. 2013; 95(13):e89 [PubMed] Article available free on PMC after 03/07/2014 Related Publications
BACKGROUND: Osteosarcoma is the most common primary bone sarcoma and affects all ages. There are substantial differences in management and outcomes for patients who have localized disease compared with distant spread at the time of diagnosis. Our goal was to examine potential risk factors predictive of metastatic disease at presentation. METHODS: The Surveillance, Epidemiology, and End Results (SEER) Program database was used to identify all patients diagnosed with osteosarcoma from 2000 to 2008 and to classify each patient as having metastatic or localized disease at the time of diagnosis. Patient-based characteristics, tumor characteristics, and county-level socioeconomic measures were analyzed to determine which factors were predictive of an increased rate of distant metastatic disease at presentation. These factors were analyzed as univariate characteristics as well as in a multivariate logistic regression model. RESULTS: We identified 2017 cases of high-grade osteosarcoma, and 464 (23.0%) of the patients presented with metastatic disease. In the unadjusted logistic regression analysis, patients had increased odds of metastatic disease at presentation if they had an age of sixty years or more (odds ratio [OR] = 2.22; 95% confidence interval [CI], 1.71 to 2.89), had a tumor located in the axial skeleton (OR = 2.47; 95% CI, 1.88 to 3.26), and lived in a county with low socioeconomic status (OR = 1.59; 95% CI, 1.08 to 2.35). These factors remained significant when combined in multivariate models controlling for age, location, and socioeconomic status. For patients with recorded tumor size information (n = 1398), the odds of metastasis at presentation increased by 10% with each additional centimeter of tumor size (OR = 1.10; 95% CI, 1.08 to 1.13). When the patients with missing tumor size information were excluded, socioeconomic status was no longer a significant risk factor for metastasis at presentation in the multivariate model. CONCLUSIONS: Osteosarcoma patients with advanced age, a tumor in the axial skeleton, a larger tumor size, and a residence in a less affluent county were more likely to have metastatic disease at presentation.