Primary bone tumours are tumours that start in the bone. In contrast, secondary bone cancer is where the cancer started in another part of the body but has then spread to the bones.
The most common types of primary bone tumour are osteosarcoma and Ewing's sarcoma, both of which are most frequently diagnosed in children and young adults. Other less common types of bone cancer include: Chondrosarcoma (a cancer arising in cartilage cells, usually found in adults between ages 50-75, though the less common mesenchymal-chondrosarcoma is more frequent in younger patients), Malignant Fibrous Histiocytoma of bone (MFH), Chondoma (a rare low grade malignancy occuring mostly between ages 30 -70), and other rare tumours.
Cancer Research UK CancerHelp information is examined by both expert and lay reviewers. Content is reviewed every 12 to 18 months. Further info. Statistics for the UK, including incidence, mortality, survival, risk factors and stats related to treatment and symptom relief.
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.
Newcastle upon Tyne Hospitals NHS Foundation Trust One of the 5 specialist centres in England funded for the investigation and surgical treatment of primary bone tumours. Patients come from the North East of England, Cumbria, Yorkshire and beyond.
PubMed Central search for free-access publications about Bone Cancer (primary) MeSH term: Bone Neoplasms US National Library of Medicine PubMed has over 22 million citations for biomedical literature from MEDLINE, life science journals, and online books. Constantly updated.
Cancer Research UK CancerHelp information is examined by both expert and lay reviewers. Content is reviewed every 12 to 18 months. Further info. Statistics for the UK, including incidence, mortality, survival, risk factors and stats related to treatment and symptom relief.
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.
BioMed Central an open access, peer-reviewed journal that considers articles on all aspects of cancer research, including the pathophysiology, prevention, diagnosis and treatment of cancers. The journal welcomes submissions concerning molecular and cellular biology, genetics, epidemiology, and clinical trials.
Membership organisation for medics in the USA and Canada
Newcastle Sarcoma Notes This Prezi attempts to summarise all the aspiring orthopaedic surgeon needs to know about Orthopaedic Oncology. By Craig Gerrand, a Consultant Orthopaedic Surgeon. Licensed for Educational Use only.
A site by Dr. James Wittig, Chief of Orthopedic Oncology at Mount Sinai Medical Center, NY. The site has many case studies including annotated images of presenting radiology, gross pathology, microscopic pathology and surgery.
This list of publications is regularly updated (Source: PubMed).
Zhao S, Lu N, Chai Y, Yu X Rapamycin inhibits tumor growth of human osteosarcomas. J BUON. 2015 Mar-Apr; 20(2):588-94 [PubMed] Related Publications
PURPOSE: Treatment options for osteosarcoma are limited due to its resistance to chemotherapy and radiotherapy. Signaling through the mammalian target of rapamycin (mTOR) pathway contributes to cell proliferation and chemoresistance of many cancers. Rapamycin, as an inhibitor of mTOR, has been developed as potentially valuable therapeutic agent. In this report, we evaluated the effects of rapamycin on human osteosarcoma cells' growth in vitro and in vivo. METHODS: Proliferation of osteosarcoma cells treated with rapamycin at different time periods was detected and changes in the cell cycle were measured by MTS and flow cytometry, respectively. Autophagy induced by rapamycin in osteosarcoma cells and the expression of cell cycle regulating proteins were detected by Western blotting. The effect of rapamycin on tumor growth in vivo was detected using mice xenograph models. RESULTS: The proliferation of osteosarcoma cells was signif- icantly inhibited by rapamycin treatment in a concentration-dependent manner and the cell cycle progression was impaired with G1 arrest. Rapamycin induced autophagy, increased the expression of p27 and decreased the expression of Cyclin D1. In addition, rapamycin suppressed the tumor growth in mice xenograph models. CONCLUSIONS: The potent antiproliferative activities of mTOR inhibitor rapamycin has been proven. Theses results strongly indicate that rapamycin may be a promising agent against osteosarcomas.
Mei J, Ni M, Jia GY, et al. Intermittent internal fixation with a locking plate to preserve epiphyseal growth function during limb-salvage surgery in a child with osteosarcoma of the distal femur: a case report. Medicine (Baltimore). 2015; 94(20):e830 [PubMed] Related Publications
Limb shortening is a problem associated with surgery for osteosarcoma of the lower extremity in adolescents, as the tumors frequently occur near the epiphysis. Herein we report the use of a less invasive stabilization system (LISS) and an intermittent fixation method to preserve the growth function of epiphysis in an 11-year-old patient with an osteosarcoma of the distal femur.The 11-year-old male presented with left knee enlargement and pain for 2 weeks, and magnetic resonance imaging (MRI) and biopsy were consistent with osteosarcoma of the left distal femur. After preoperative chemotherapy, en bloc tumor resection was performed with margins based on MRI findings preserving the epiphyseal growth plate, the tumor cavity was filled with inactivated bone and bone cement, and a LISS was used to stabilize the femur. Aggressive postoperative chemotherapy was given. Approximately 105 weeks after surgery radiography showed that the distal end of the plate had moved superior to the epiphysis along with bone growth. Locking screws were placed in the distal part of the LISS plate to stabilize the re-implanted bone, and external fixation was not needed.The patient was able to walk with the crutches 1 week postoperatively, and bear weight on the extremity 6 weeks postoperatively. At 6 years after surgery, the patient's height had increased 52 cm, shortening of the affected limb was only 1 cm, and the circumference of the affected limb was 2 cm smaller than that of the contralateral limb. There was no significant discomfort in the affected limb, and there was no gait abnormality. The patient could jump and run, and could participate in sports including basketball and badminton to the same degree as his peers.In summary, the novel method of bone reconstruction and fixation provided good results in a child with an osteosarcoma of the distal femur. This fixation method preserves the osteogenic function of the epiphysis and restored bone integrity simultaneously, and provides good functional recovery.
Bahk WJ, Mirra JM Differential diagnostic value of "blue reticulated chondroid-like material" in aneurysmal bone cysts: a classic histopathologic analysis of 215 cases. Am J Clin Pathol. 2015; 143(6):823-9 [PubMed] Related Publications
OBJECTIVES: Our classic histopathologic study of aneurysmal bone cyst (ABC) revealed that "blue reticulated chondroid-like material" (BRC) is characteristic of ABC. METHODS: The light microscopic findings were retrospectively analyzed in 215 cases of ABC, including 101 primary and 114 secondary cases. In addition, 22 cases of telangiectatic osteosarcoma (TOS) were drawn from the same source and used as a control. RESULTS: We found the presence of typical BRC in 24 (23.8%) of 101 cases of primary ABC and in six (5.3%) of 114 cases of secondary ABC, with an overall incidence of 30 (14%). None of the cases of TOS showed BRC. BRC was significantly more common in primary ABC than in secondary ABC (P < .05) and in patients 19 years or younger than in those 20 years or older (P < .05). CONCLUSIONS: BRC appears to be a unique histopathologic feature of ABC, making it valuable to differentiate benign ABC from TOS. Simple H&E stain can be economically performed anywhere.
Bus MP, Bramer JA, Schaap GR, et al. Hemicortical resection and inlay allograft reconstruction for primary bone tumors: a retrospective evaluation in the Netherlands and review of the literature. J Bone Joint Surg Am. 2015; 97(9):738-50 [PubMed] Related Publications
BACKGROUND: Selected primary tumors of the long bones can be adequately treated with hemicortical resection, allowing for optimal function without compromising the oncological outcome. Allografts can be used to reconstruct the defect. As there is a lack of studies of larger populations with sufficient follow-up, little is known about the outcomes of these procedures. METHODS: In this nationwide retrospective study, all patients treated with hemicortical resection and allograft reconstruction for a primary bone tumor from 1989 to 2012 were evaluated for (1) mechanical complications and infection, (2) oncological outcome, and (3) failure or allograft survival. The minimum duration of follow-up was twenty-four months. RESULTS: The study included 111 patients with a median age of twenty-eight years (range, seven to seventy-three years). The predominant diagnoses were adamantinoma (n = 37; 33%) and parosteal osteosarcoma (n = 18; 16%). At the time of review, 104 patients (94%) were alive (median duration of follow-up, 6.7 years). Seven patients (6%) died, after a median of twenty-six months. Thirty-seven patients (33%) had non-oncological complications, with host bone fracture being the most common (n = 20, 18%); all healed uneventfully. Other complications included nonunion (n = 8; 7%), infection (n = 8; 7%), and allograft fracture (n = 3; 3%). Of ninety-seven patients with a malignant tumor, fifteen (15%) had residual or recurrent tumor and six (6%) had metastasis. The risk of complications and fractures increased with the extent of cortical resection. CONCLUSIONS: Survival of hemicortical allografts is excellent. Host bone fracture is the predominant complication; however, none of these fractures necessitated allograft removal in our series. The extent of resection is the most important risk factor for complications. Hemicortical resection is not recommended for high-grade lesions; however, it may be superior to segmental resection for treatment of carefully selected tumors, provided that it is possible to obtain adequate margins. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Chow LT Fibular giant cell-rich osteosarcoma virtually indistinguishable radiographically and histopathologically from giant cell tumor-analysis of subtle differentiating features. APMIS. 2015; 123(6):530-9 [PubMed] Related Publications
Giant cell-rich osteosarcoma by its abundance of osteoclastic giant cells and paucity of tumor osteoid, leads to its easy confusion with giant cell tumor during biopsy interpretation. In this report, we describe a unique case of upper fibular metaphyseal giant cell-rich osteosarcoma in a 12-year-old boy; the radiographic and histopathologic features of the biopsy and initial resected tumor are virtually indistinguishable from conventional giant cell tumor. The tumor rapidly recurred 7 months after resection with metastasis to the groin lymph nodes, was resistant to first-line chemotherapy and pursued an aggressive course, developing disseminated metastasis to the lung, liver, pelvis, scapula and clavicle, and resulted in the death of the patient 21 months after initial presentation. The subtle features alerting one to the possibility of giant cell-rich osteosarcoma are retrospectively evaluated in comparison with cases of metaphyseal conventional giant cell tumors, four from our records and those from literature review. We conclude that the occurrence of a giant cell-rich lesion in the metaphysis of a skeletally immature individual merits careful assessment for the presence of periosteal reaction, permeative infiltrative margins, lacelike osteoid formation, high mitotic activity or Ki67 proliferative index, and extra-tumoral lymphovascular permeation, since the possibility of an aggressive lesion notably giant cell-rich osteosarcoma probably increases with the number of such features.
Mirabello L, Yeager M, Mai PL, et al. Germline TP53 variants and susceptibility to osteosarcoma. J Natl Cancer Inst. 2015; 107(7) [PubMed] Related Publications
The etiologic contribution of germline genetic variation to sporadic osteosarcoma is not well understood. Osteosarcoma is a sentinel cancer of Li-Fraumeni syndrome (LFS), in which approximately 70% of families meeting the classic criteria have germline TP53 mutations. We sequenced TP53 exons in 765 osteosarcoma cases. Data were analyzed with χ(2) tests, logistic regression, and Cox proportional hazards regression models. We observed a high frequency of young osteosarcoma cases (age <30 years) carrying a known LFS- or likely LFS-associated mutation (3.8%) or rare exonic variant (5.7%) with an overall frequency of 9.5%, compared with none in case patients age 30 years and older (P < .001). This high TP53 mutation prevalence in young osteosarcoma cases is statistically significantly greater than the previously reported prevalence of 3% (P = .0024). We identified a novel association between a TP53 rare variant and metastasis at diagnosis of osteosarcoma (rs1800372, odds ratio = 4.27, 95% confidence interval = 1.2 to 15.5, P = .026). Genetic susceptibility to young onset osteosarcoma is distinct from older adult onset osteosarcoma, with a high frequency of LFS-associated and rare exonic TP53 variants.
Most primitive neuroectodermal tumor of the chest wall destroy the rib, chest wall muscles, diaphragm, and lung or extend into the spinal compartment, resulting in a large-sized tumor and symptoms. In contrast, we recently encountered a rare case of Askin's tumor presenting with early-onset chest pain despite the small size. After resection of the tumor and adjuvant chemotherapy, the patient remains disease-free over 3 years of follow-up.
Niu G, Li B, Sun J, Sun L miR-454 is down-regulated in osteosarcomas and suppresses cell proliferation and invasion by directly targeting c-Met. Cell Prolif. 2015; 48(3):348-55 [PubMed] Related Publications
OBJECTIVES: Osteosarcoma is the most common primary bone malignancy of children and young adults. Increasing evidence has shown that microRNAs (miRNAs) are associated with cancer development, but, little is known concerning the role of miR-454 in osteosarcoma. MATERIALS AND METHODS: qRT-PCR was performed to detect expression of miR-454 in osteosarcoma cell lines and tissues. To understand its role in osteosarcoma, we reintroduced expression of miR-454 in the MG-63 cell line by transfection with miR-454 mimics or inhibitors. CCK-8 assay and an invasion assay were used to detect the functional role of miR-454. Luciferase assay and western blot analysis were performed to detect the target gene of miR-454. RESULTS: miR-454 was found to be down-regulated in osteosarcoma tissues and cell lines. Its over-expression inhibited tumour growth and invasion and its down-regulation promoted cell proliferation and invasion. Subsequent investigation revealed that c-Met was a direct and functional target of miR-454 in osteosarcoma. Overexpression of miR-454 impaired c-Met-induced cell proliferation and invasion. Finally, miR-454 was found to be inversely correlated to c-Met expression in human osteosarcoma tissues. CONCLUSIONS: Reduced-expression of miR-454 in osteosarcoma cells promoted tumour growth by targeting c-Met, thus miR-454 may be a potential therapy target for this tumour.
He JY, Xi WH, Zhu LB, et al. Knockdown of Aurora-B alters osteosarcoma cell malignant phenotype via decreasing phosphorylation of VCP and NF-κB signaling. Tumour Biol. 2015; 36(5):3895-902 [PubMed] Related Publications
The aim of this study is to investigate the effects of inhibiting Aurora-B on osteosarcoma (OS) cell malignant phenotype, phosphorylation of valosin-containing protein (VCP), and the activity of NF-κB signaling in vitro. The expressions of Aurora-B and p-VCP proteins were detected by immunohistochemistry in 24 OS tissues, and the relationship between Aurora-B and p-VCP was investigated. The results showed that there was a positive correlation between Aurora-B and p-VCP proteins. The expression of Aurora-B in human OS cell lines U2-OS and HOS cells was inhibited by specific short hairpin RNA (shRNA) lentivirus (AURKB-shRNA lentivirus, Lv-shAURKB) which targeted Aurora-B. The results showed that the phosphorylation of VCP, the activity of NF-κB signaling pathway and the malignant phenotype of OS cells were all suppressed by knockdown of Aurora-B. It indicated that the inhibition of Aurora-B alters OS cells malignant phenotype by downregulating phosphorylation of VCP and activating of the NF-κB signaling pathway in vitro.
Jiang Y, Ludwig J, Janku F Targeted therapies for advanced Ewing sarcoma family of tumors. Cancer Treat Rev. 2015; 41(5):391-400 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
The prognosis of adolescent and young adult patients battling metastatic Ewing sarcoma family of tumors (ESFT) remains less than 30% despite the development of systemic therapies. In the era of personalized medicine, novel molecular targets have been tested in preclinical or clinical settings in ESFT. In this review, we focus on early clinical and translational research that identified multiple molecular targets, including IGF-1R; mTOR; tyrosine kinase inhibitors; EWS-FLI1-related targets, and others. Overall, novel targeted therapies demonstrated modest efficacy; however pronounced and durable antineoplastic responses have been observed in small subsets of treated patients, for example with IGF-1R antibodies. Identifying outcome-predicting biomarkers and overcoming treatment resistance remain major challenges. Due to the rarity of ESFT, multi-institutional collaboration efforts of clinicians, basic and translational scientists are needed in order to understand biology of therapeutic response or resistance, which can lead to development of novel therapeutic methods and improved patient outcomes.
Buchtova M, Chaloupkova R, Zakrzewska M, et al. Instability restricts signaling of multiple fibroblast growth factors. Cell Mol Life Sci. 2015; 72(12):2445-59 [PubMed] Related Publications
Fibroblast growth factors (FGFs) deliver extracellular signals that govern many developmental and regenerative processes, but the mechanisms regulating FGF signaling remain incompletely understood. Here, we explored the relationship between intrinsic stability of FGF proteins and their biological activity for all 18 members of the FGF family. We report that FGF1, FGF3, FGF4, FGF6, FGF8, FGF9, FGF10, FGF16, FGF17, FGF18, FGF20, and FGF22 exist as unstable proteins, which are rapidly degraded in cell cultivation media. Biological activity of FGF1, FGF3, FGF4, FGF6, FGF8, FGF10, FGF16, FGF17, and FGF20 is limited by their instability, manifesting as failure to activate FGF receptor signal transduction over long periods of time, and influence specific cell behavior in vitro and in vivo. Stabilization via exogenous heparin binding, introduction of stabilizing mutations or lowering the cell cultivation temperature rescues signaling of unstable FGFs. Thus, the intrinsic ligand instability is an important elementary level of regulation in the FGF signaling system.
Humm JL, Sartor O, Parker C, et al. Radium-223 in the treatment of osteoblastic metastases: a critical clinical review. Int J Radiat Oncol Biol Phys. 2015; 91(5):898-906 [PubMed] Related Publications
The element radium (Ra) was discovered by the Curies in 1898 and within a decade was in broad scientific testing for the management of several forms of cancer. The compound was known to give rise to a series of both high-energy particulate and penetrating γ-emissions. The latter found an important role in early 20th century brachytherapy applications, but the short-range α-particles seemed much less useful. Although highly cytotoxic when released within a few cell diameters of critical cell nuclei, the dense double-strand break damage was poorly repaired, and concerns regarding treatment-related toxicities and secondary malignancies halted clinical development. Moreover, the most common isotope of Ra has an exceptionally long half-life (>1600 years for (226)Ra) that proved daunting when aiming for a systemic cancer therapy. Fortunately, other radium isotopes have more convenient half-lives while still producing cytotoxic α particles. Radium-223 dichloride has a half-life of 11.4 days, and this isotope was identified as an excellent candidate for radionuclide therapy of cancers metastatic to bone. The calcium-mimetic chemical properties of the radium allowed intravenous infusion with rapid uptake to sites of new bone formation. The highly efficient bone localization suggested a potential therapeutic role for osteoblastic bone metastases, and a series of phase 1, 2, and 3 clinical trials was undertaken to explore this possibility. This series of clinical explorations culminated in the ALSYMPCA trial, an international, placebo-controlled, phase 3 study that accrued 921 symptomatic men with bone-metastatic, castrate-resistant prostate cancer. Results of this trial demonstrated a prolongation of overall survival, and regulatory agencies around the world have now approved this product as a treatment for advanced prostate cancer.
Jian Y, Tian X, Li B, et al. Letter regarding Li JS et al. entitled "ERCC polymorphisms and prognosis of patients with osteosarcoma". Tumour Biol. 2015; 36(5):3195-6 [PubMed] Related Publications
With great interest, we read the article "ERCC polymorphisms and prognosis of patients with osteosarcoma" (by Li JS et al.), which has reached important conclusions about the relationship between ERCC polymorphisms and osteosarcoma prognosis. Through quantitative analysis, the meta-analysis showed that ERCC2 Lys751Gln (ORGG vs. AA = 0.40 (95%CI = 0.1-0.86), P heterogeneity = 0.502; I (2) = 0 %) and ERCC5 His46His (ORCC vs. TT = 0.37 (95%CI = 0.15-0.93), P heterogeneity = 0.569; I (2) = 0 %) polymorphisms might influence the prognosis of patients with osteosarcoma . The meta-analysis results are encouraging. Nevertheless, some deficiencies still existed that we would like to raise.
Imtiaz S, Kazmi A Patterns of care and outcomes of adult osteosarcoma in a tertiary care cancer centre in Pakistan. J Pak Med Assoc. 2014; 64(10):1166-70 [PubMed] Related Publications
OBJECTIVE: To present our experience of treatment outcomes in adult osteosarcoma patients. METHODS: The retrospective study was conducted at the Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, and comprised data related to 74 adult patients with osteosarcoma from 1995 to 2009. The treatment plan consisted of surgery preceded by neo-adjuvant chemotherapy followed by adjuvant chemotherapy. SPSS 16 was used for statistical analysis. RESULTS: Of the 74 patients in the study, 58 (78%) were in the 18-29 age group with an overall male-to-female ratio of 3:1. The commonest site of disease was femur, 30 (43%). Of the 66 (89%) patients undergoing definitive surgery, 59 (89.4%) had amputation. The remaining 7 (10.6%) limb salvage operations were in the neo-adjuvant chemotherapy group. Good histopathological response rates in high-dose methotrexate containing regimens and other regimens were similar with an overall good response rate of 18/51 (35%). The commonest site of relapse was lung.Twelve out of 27 (44%) patients with lung-only metastases underwent successful metastatectomy. For patients with localised disease at presentation 3-year event-free survival was 30%, and 3-year overall survival was 71%. For patients with metastases at presentation 3-year overall survival was 45%. Median overall survival for patients receiving high-dose methotrexate and other regimens was 1.7 years vs 2.9 years. CONCLUSION: Adult osteosarcoma treated with cisplatin/doxorubicin based chemotherapy and surgery had good outcomes. The role of high-dose methotrexate in adult osteosarcoma remains uncertain.
Gonçalves C, Martins-Neves SR, Paiva-Oliveira D, et al. Sensitizing osteosarcoma stem cells to doxorubicin-induced apoptosis through retention of doxorubicin and modulation of apoptotic-related proteins. Life Sci. 2015; 130:47-56 [PubMed] Related Publications
AIMS: Osteosarcoma is the most common pediatric bone malignancy with high propensity to metastasize and relapse. Emerging evidence suggest that osteosarcoma is sustained by a subset of self-renewing cancer stem like cells (CSCs) relying on mechanisms to evade apoptosis and survive in response to drugs-induced DNA damage. We proposed to decipher the mechanisms underlying the resistance of CSCs to doxorubicin-induced apoptosis. MAIN METHODS: CSCs were isolated using a sphere-forming assay and tested for sensitivity to doxorubicin-induced apoptosis, using MTT cell viability and BrdU proliferation assays, TUNEL staining and caspases 3/7 activity. Bcl-2 family proteins were analyzed by Western blot. Doxorubicin uptake was determined by confocal microscopy and bioluminescence imaging. KEY FINDINGS: We showed that osteosarcoma sphere stem-like cells expressed the multidrug-related efflux transporters P-glycoprotein and BCRP and are highly resistant to doxorubicin-induced apoptosis. Conversely after exposure to doxorubicin, these cells displayed an up-regulation of the anti-apoptotic proteins Bcl-2 and Bcl-xL with concomitant down-regulation of Bak and decreased caspase 3/7 activity. Inhibition of drug efflux transporters enhanced the cellular uptake of doxorubicin, being encompassed by an up-regulation the pro-apoptotic protein Bak and suppression of Bcl-2, favoring the commitment of CSCs towards apoptosis. SIGNIFICANCE: These results seemingly suggest that the high apoptotic threshold of CSCs to doxorubicin-induced cell dead stimuli is mainly dependent on the drug concentration reaching tumor cells that are governed by efflux transporter activity. Therefore, modulation of these transporters may be effective in potentiating the proapoptotic effects of doxorubicin, and emerges as an attractive strategy to sensitize osteosarcoma CSCs to chemotherapy.
Yu H, Sun H, Bai Y, et al. MEF2D overexpression contributes to the progression of osteosarcoma. Gene. 2015; 563(2):130-5 [PubMed] Related Publications
The underlying molecular pathogenesis of osteosarcoma remains poorly understood. The transcription factor MEF2D promotes the survival of various types of cells and functions as an oncogene in liver cancer. However, its potential contribution to osteosarcoma has not been explored. In this study, we investigated MEF2D expression and function in osteosarcoma, finding that MEF2D elevation in osteosarcoma clinical specimens was associated with patients' poor prognosis. MEF2D suppression was shown to decrease the proliferation of osteosarcoma cells, while forced expression of MEF2D was able to promote the proliferation of normal bone fibroblast. Notably, MEF2D silencing abolished osteosarcoma tumorigenicity in an animal model. Mechanistic investigations revealed that MEF2D silencing triggered G2-M arrest in osteosarcoma cells by suppressing RPRM and CDKN1A. miR-144 was found to suppress the expression of MEF2D in osteosarcoma cells. Collectively, our results demonstrated that MEF2D is a candidate oncogene for osteosarcoma and a potential molecular target for cancer therapy.
Lee RJ, Arshi A, Schwartz HC, Christensen RE Characteristics and prognostic factors of osteosarcoma of the jaws: a retrospective cohort study. JAMA Otolaryngol Head Neck Surg. 2015; 141(5):470-7 [PubMed] Related Publications
IMPORTANCE: Osteosarcoma of the jaws is rare and clinically distinct from osteosarcoma of the long bones of the body with different treatment and outcomes. The literature on these tumors is limited to case reports and small case series mostly from single institutions. We used data from the population-based national Surveillance, Epidemiology and End Results (SEER) cancer registry to determine the epidemiology and prognostic factors associated with osteosarcoma of the jaws. OBJECTIVE: To investigate the epidemiologic characteristics and prognostic factors for survival in patients diagnosed with osteosarcoma of the jaws. DESIGN, SETTING, AND PARTICIPANTS: A retrospective, population-based cohort study of 541 patients in the SEER tumor registry diagnosed with osteosarcoma of the jaws from 1973 through 2011 were reviewed. EXPOSURES: Patients had been treated with surgery, radiation, both, or neither. MAIN OUTCOMES AND MEASURES: Overall and disease-specific survival. RESULTS: A total of 541 patients diagnosed with osteosarcoma of the jaws were identified (49.9% male and 50.1% female, with a mean age of 41.3 years). Kaplan-Meier analysis demonstrated an overall survival (OS) and disease-specific survival (DSS) of 53% and 62%, respectively, at 5 years and 35% and 54%, respectively, at 10 years. Multivariate Cox regression analysis revealed that independent predictors of OS and DSS included age at diagnosis (hazard ratio [HR], 1.03; 95% CI, 1.02-1.04 [P < .001] for OS; and HR, 1.03; 95% CI, 1.02-1.05 [P < .001] for DSS); stage at presentation (HR, 1.37; 95% CI, 1.10-1.71 [P = .006] for OS; and HR, 1.34; 95% CI, 1.01-1.76 [P = .04] for DSS); and surgical resection (HR, 0.31; 95% CI, 0.16-0.60 [P < .001] for OS; and HR, 0.22; 95% CI, 0.09-0.56 [P = .001] for DSS). Tumor size was not significant for OS (HR, 1.00; 95% CI, 1.00-1.01 [P = .11] but significant for DSS (HR, 1.01; 95% CI, 1.00-1.01 [P = .003]). CONCLUSIONS AND RELEVANCE: To our knowledge, this is the largest study to date investigating prognostic factors for survival in patients diagnosed with osteosarcoma of the jaws. Determinants of survival include age at diagnosis, stage at presentation, tumor size, and surgical therapy. Radiation therapy was not associated with improved survival, reflecting the controversy surrounding its use in clinical literature.
Sonnemann J, Grauel D, Blümel L, et al. RETRA exerts anticancer activity in Ewing's sarcoma cells independent of their TP53 status. Eur J Cancer. 2015; 51(7):841-51 [PubMed] Related Publications
Mutant p53 can exert oncogenic activity by inhibitory interaction with p73. The small-molecule RETRA has been described to disrupt this interaction and to suppress carcinoma cells (Kravchenko et al., 2008). RETRA's anticancer activity was restricted to tumour cells bearing mutant p53; it was not active in p53 negative and in p53 wild-type cells. Here, we explored the responsiveness of Ewing's sarcoma (ES) cells with mutant p53 to RETRA. For comparison, we also tested RETRA in p53 null and in p53 wild-type ES cells. We found RETRA to be effective in the three mutant p53 ES cell lines investigated. Strikingly, however, RETRA was similarly effective in the p53-deficient and in the two p53 wild-type ES cell lines examined. RETRA elicited apoptosis, as assessed by flow cytometric analyses of mitochondrial depolarisation and DNA fragmentation, caspase 3/7 activity assay and PARP-1 cleavage immunodetection, and G2/M cell cycle arrest completely independent of the cellular TP53 status. In contrast, various p53-deficient and -proficient carcinoma, osteosarcoma and leukaemia cells were unresponsive to RETRA. RETRA also induced gene expression of p53 target genes PUMA and p21 in ES cells irrespective of their TP53 status. These in vitro findings provide a rationale for an in vivo exploration of RETRA's potential as an effective therapeutic approach for patients with ES.
Tang C, Zhao Y, Huang S, et al. Influence of Artemisia annua extract derivatives on proliferation, apoptosis and metastasis of osteosarcoma cells. Pak J Pharm Sci. 2015; 28(2 Suppl):773-9 [PubMed] Related Publications
Regarding the Artemisia annua extract derivatives called dihydroarteminin (DHA) as the object, we studied about its influence to the proliferation, apoptosis and metastasis of human osteosarcoma cells. First, we cultured in vitro the osteosarcoma cell strain and divided them into groups, then detected the cell proliferation, apoptosis and cell metastasis, etc by multiple measurement technique. Finally, we observed the influence of DHA to human osteosarcoma cells. Osteosarcoma cells were all sensitive to DHA, and the appropriate concentration range was 10~40μM. DHA could effectively restrain its protein expression, and there was a significant difference between experimental group and control group. These finding suggest that, the Artemisia annua extract derivatives (DHA) has a biological effect of observably restraining the proliferation and metastasis of human osteosarcoma cells and promoting the tumour cell apoptosis.
Meyliker RG, Strauss RA Periosteal osteosarcoma of the mandible: a case report. J Oral Maxillofac Surg. 2015; 73(4):787.e1-4 [PubMed] Related Publications
This report describes a rare case of a periosteal osteosarcoma of the mandible in a 50-year-old African-American woman who showed no underlying bony changes at panoramic radiography or computed tomography. This report describes the diagnostic workup used to obtain the definitive diagnosis and the surgical treatment and recommended method for subsequent tumor surveillance. Emphasis is placed on distinguishing periosteal osteosarcomas as a separate entity from conventional intraosseous osteosarcomas in the head and neck region.
Shen J, LaChaud G, Khadarian K, et al. NELL-1 expression in benign and malignant bone tumors. Biochem Biophys Res Commun. 2015; 460(2):368-74 [PubMed] Related Publications
NELL-1 (NEL-like Protein 1) is an osteoinductive protein with increasing usage as a bone graft substitute in preclinical animal models. NELL-1 was first identified to have bone-forming properties by its overexpression in fusing cranial sutures. Since this time, addition of recombinant NELL-1 has been used to successfully induce bone formation in the calvarial, axial and appendicular skeleton. With increasing interest in the use of NELL-1 as a bone-graft substitute, we sought to examine the expression of NELL-1 in a wide spectrum of benign and malignant bone-forming skeletal tumors. Immunohistochemical expression was examined in human pathologic specimens. Quantitative RT-PCR evaluated NELL-1 expression among OS cell lines in vitro. Results showed NELL-1 expression in all bone tumors. Likewise, all OS cell lines demonstrated increased NELL-1 expression in comparison to non-lesional human bone marrow stromal cells. Among, benign bone tumors (osteoid osteoma and osteoblastoma), strong and diffuse staining was observed, which spatially correlated with markers of osteogenic differentiation. In contrast, a relative reduction in NELL-1 staining was observed in osteosarcoma, accompanied by increased variation between tumors. Among osteosarcoma specimens, NELL-1 expression did not correlate well with markers of osteogenic differentiation. Surprisingly, among osteosarcoma subtypes, fibroblastic osteosarcoma demonstrated the highest expression of NELL-1. In summary, NELL-1 demonstrates diffuse and reliable expression in benign but not malignant bone-forming skeletal tumors. Future studies will further define the basic biologic, diagnostic and prognostic importance of NELL-1 in bone neoplasms.
Zhu J, Gu J, Ma J, et al. Histone deacetylase inhibitors repress chondrosarcoma cell proliferation. J BUON. 2015 Jan-Feb; 20(1):269-74 [PubMed] Related Publications
PURPOSE: Due to the high resistance to conventional therapy, there is still no convincingly effective treatment for chondrosarcoma. As a promising new treatment strategy, histone deacetylase inhibitors (HDACIs) have been reported to induce cell arrest, apoptosis and differentiation in some kinds of malignancies, but how HDACi exert their effects on chondrosarcoma is not well understood yet. METHODS: We investigated the effects of HDACIs trichostatin A (TSA) and sodium valproate (VPA) on chondrosarcoma cells in vitro and in vivo. The cell proliferation and cell cycle were examined in two chondrosarcoma cell lines, SW1353 and JJ012, by MTS and flow cytometry assays, respectively. The in vivo effects of HDACIs were investigated by assessing the chondrosarcoma growth in a mouse xenograft model. RESULTS: Our results showed that TSA and VPA significantly repressed the proliferation of chondrosarcoma cells in a concentration-dependent manner. Flow cytometry indicated that TSA arrested the cell cycle in G2/M phase and VPA arrested the cell cycle in G1 phase. The tumor growth was markedly suppressed in mice treated with TSA and VPA. CONCLUSIONS: HDACIs significantly repress the proliferation of chondrosarcoma cells in vitro and in vivo. Our findings imply that HDACIs may provide a novel therapeutic target for the treatment of chondrosarcoma.
Pan HY, Morani A, Wang WL, et al. Prognostic factors and patterns of relapse in ewing sarcoma patients treated with chemotherapy and r0 resection. Int J Radiat Oncol Biol Phys. 2015; 92(2):349-57 [PubMed] Article available free on PMC after 01/06/2016 Related Publications
PURPOSE: To identify prognostic factors and patterns of relapse for patients with Ewing sarcoma who underwent chemotherapy and R0 resection without radiation therapy (RT). METHODS AND MATERIALS: We reviewed the medical records of patients who underwent surgical resection at our institution between 2000 and 2013 for an initial diagnosis of Ewing sarcoma. The associations of demographic and clinical factors with local control (LC) and patient outcome were determined by Cox regression. Time to events was measured from the time of surgery. Survival curves were estimated by the Kaplan-Meier method and compared by the log-rank test. RESULTS: A total of 66 patients (median age 19 years, range 4-55 years) met the study criteria. The median follow-up was 5.6 years for living patients. In 43 patients (65%) for whom imaging studies were available, the median tumor volume reduction was 73%, and at least partial response by Response Evaluation Criteria in Solid Tumors was achieved in 17 patients (40%). At 5 years, LC was 78%, progression-free survival (PFS) was 59%, and overall survival (OS) was 65%. Poor histologic response (necrosis ≤95%) was an independent predictor of LC (hazard ratio [HR] 6.8, P=.004), PFS (HR 5.2, P=.008), and OS (HR 5.0, P=.008). Metastasis on presentation was also an independent predictor of LC (HR 6.3, P=.011), PFS (HR 6.8, P=.002), and OS (HR 6.7, P=.002). Radiologic partial response was a predictor of PFS (HR 0.26, P=.012), and postchemotherapy tumor volume was associated with OS (HR 1.06, P=.015). All deaths were preceded by distant relapse. Of the 8 initial local-only relapses, 5 (63%) were soon followed by distant relapse. Predictors of poor postrecurrence survival were time to recurrence <1 year (HR 11.5, P=.002) and simultaneous local and distant relapse (HR 16.8, P=.001). CONCLUSIONS: Histologic and radiologic response to chemotherapy were independent predictors of outcome. Additional study is needed to determine the role of adjuvant radiation therapy for patients who have poor histologic response after R0 resection.
Wodajo FM Top five lesions that do not need referral to orthopedic oncology. Orthop Clin North Am. 2015; 46(2):303-14 [PubMed] Related Publications
Patients with potential bone and soft tissue tumors can be challenging for orthopedic surgeons. Lesions that appear benign can still create anxiety for the clinician and patient. However, attention to a few key imaging and clinical findings is enough to correctly diagnose five of the most common bone and soft tissue lesions: lipoma, enchondroma, osteochondroma, nonossifying fibroma, and Paget disease. Accurate identification of these lesions should be within the scope of most orthopedic surgeons and, because most of these patients will not need surgical treatment, referral to orthopedic oncology will not typically be required.
Tang G, Zhang Z, Qian H, et al. (-)-Epigallocatechin-3-gallate inhibits osteosarcoma cell invasiveness by inhibiting the MEK/ERK signaling pathway in human osteosarcoma cells. J Environ Pathol Toxicol Oncol. 2015; 34(1):85-93 [PubMed] Related Publications
The notorious lung metastatic capability of osteosarcoma aggravates patient mortality and remains the primary challenge to be overcome. We investigated the effect of (-)-epigallocatechin-3-gallate (EGCG) on the metastasis capability of osteosarcoma cells. We performed cytotoxicity assays (MTT) to determine the appropriate concentration of EGCG for experiments. Migration, invasion, wound-healing, and adhesion assays were performed to assess the effect of EGCG on the metastasis of osteosarcoma. Changes in the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway were investigated using Western blot analyses. In addition, a MEK inhibitor (U0126) was used in invasion assays to determine the effect of the MEK/ERK signaling pathway. We found that EGCG may markedly inhibit the migration and invasion capacity of osteosarcoma cells, which occurred concurrently with inhibition of the expression of phospho-MEK and phospho-ERK. Inhibitors of MEK inhibited the invasion of osteosarcoma cells, and this effect could be enhanced by EGCG. We also detected the expression of c-Jun N-terminal kinase, p38, and their respective phospho-proteins, but did not find any meaningful changes. Taken together, our results demonstrated that EGCG could inhibit the metastasis capability of osteosarcoma cells by inhibiting MEK/ERK signaling activity and may provide new therapeutic value for osteosarcoma.
Musso N, Caronia FP, Castorina S, et al. Somatic loss of an EXT2 gene mutation during malignant progression in a patient with hereditary multiple osteochondromas. Cancer Genet. 2015; 208(3):62-7 [PubMed] Related Publications
Multiple osteochondromas (MO) is an autosomal-dominant skeletal disorder caused by mutations in the exostosin-1 (EXT1) or exostosin-2 (EXT2) genes. In this study, we report the analysis of the mutational status of the EXT2 gene in tumor samples derived from a patient affected by hereditary MO, documenting the somatic loss of the germline mutation in a giant chondrosarcoma and in a rapidly growing osteochondroma. The sequencing of all exons and exon-intron junctions of the EXT1 and EXT2 genes from blood DNA of the proband did not reveal any mutation in the EXT1 gene but did demonstrate the presence of the transition point mutation c.67C > T in the EXT2 gene, determining the introduction of a stop codon in the coding sequence (p.Arg23*). A mutational analysis of other members of the family and the presence of osteochondromas in the metaphysis of long bones confirmed the diagnosis of hereditary multiple osteochondromas. Direct sequencing from DNA extracted from different sites of two tumor samples (a small rapidly growing osteochondroma and a giant peripheral secondary chondrosarcoma, each located at different chondrocostal junctions) revealed the loss of the germline EXT2 mutation. Analysis of microsatellite polymorphic markers in the 11p region harboring the EXT2 gene did not reveal any loss of heterozygosity. This observation supports a recent model of sarcomagenesis in which osteochondroma cells bear EXT homozygous inactivation, whereas chondrosarcoma-initiating cells are EXT-expressing cells.
Tsuru A, Setoguchi T, Matsunoshita Y, et al. Hairy/enhancer-of-split related with YRPW motif protein 1 promotes osteosarcoma metastasis via matrix metallopeptidase 9 expression. Br J Cancer. 2015; 112(7):1232-40 [PubMed] Article available free on PMC after 31/03/2016 Related Publications
BACKGROUND: Activation of the Notch pathway has been reported in various types of cancers. However, the role of the hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1) in osteosarcoma is unknown. We examined the function of HEY1 in osteosarcoma. METHODS: Expression of HEY1 was studied in human osteosarcoma. The effects of HEY1 in osteosarcoma were evaluated in vitro and in a xenograft model. Moreover, we examined the function of matrix metallopeptidase 9 (MMP9) as a downstream effector of HEY1. RESULTS: HEY1 was upregulated in human osteosarcoma. Knockdown of HEY1 inhibited the invasion of osteosarcoma cell lines. In contrast, the forced expression of HEY1 increased the invasion of mesenchymal stem cell. In addition, lung metastases were significantly inhibited by the knockdown of HEY1. We found that MMP9 was a downstream effector of HEY1 that promotes the invasion of osteosarcoma cells. Knockdown of HEY1 decreased the expression of MMP9. Addition of MMP9 rescued the invasion of osteosarcoma cells that had been rendered less invasive by knockdown of HEY1 expression. CONCLUSIONS: Our findings suggested that HEY1 augmented the metastasis of osteosarcoma via upregulation of MMP9 expression. Therefore, inhibition of HEY1 may be a novel therapeutic strategy for preventing osteosarcoma metastasis.
Tzeng HE, Chen PC, Lin KW, et al. Basic fibroblast growth factor induces VEGF expression in chondrosarcoma cells and subsequently promotes endothelial progenitor cell-primed angiogenesis. Clin Sci (Lond). 2015; 129(2):147-58 [PubMed] Related Publications
Chondrosarcoma, a common malignant tumour, develops in bone. Effective adjuvant therapy remains inadequate for treatment, meaning poor prognosis. It is imperative to explore novel remedies. Angiogenesis is a rate-limiting step in progression that explains neovessel formation for blood supply in the tumour microenvironment. Numerous studies indicate that EPCs (endothelial progenitor cells) promote angiogenesis and contribute to tumour growth. bFGF (basic fibroblast growth factor), a secreted cytokine, regulates biological activity, including angiogenesis, and correlates with tumorigenesis. However, the role of bFGF in angiogenesis-related tumour progression by recruiting EPCs in human chondrosarcoma is rarely discussed. In the present study, we found that bFGF induced VEGF (vascular endothelial growth factor) expression via the FGFR1 (fibroblast growth factor receptor 1)/c-Src/p38/NF-κB (nuclear factor κB) signalling pathway in chondrosarcoma cells, thereby triggering angiogenesis of endothelial progenitor cells. Our in vivo data revealed that tumour-secreted bFGF promotes angiogenesis in both mouse plug and chick CAM (chorioallantoic membrane) assays. Xenograft mouse model data, due to bFGF-regulated angiogenesis, showed the bFGF regulates angiogenesis-linked tumour growth. Finally, bFGF was highly expressed in chondrosarcoma patients compared with normal cartilage, positively correlating with VEGF expression and tumour stage. The present study reveals a novel therapeutic target for chondrosarcoma progression.
Zhang Y, Duan G, Feng S MicroRNA-301a modulates doxorubicin resistance in osteosarcoma cells by targeting AMP-activated protein kinase alpha 1. Biochem Biophys Res Commun. 2015; 459(3):367-73 [PubMed] Related Publications
MicroRNAs have been implicated in drug resistance of osteosarcoma (OS). MicroRNA-301a (miR-301a) is up-regulated and functions as an oncogene in various cancers. However, little is known about the role of miR-301a in drug resistance of OS cells. In this study, we found that doxorubicin induced time-dependent expression of miR-301a in OS cells. Meantime, doxorubicin promoted HMGCR expression and inhibited AMPKα1 expression, which was further facilitated by miR-301a overexpression. Luciferase reporter assay identified AMPKα1 as direct target gene of miR-301a. Notably, miR-301a reduced doxorubicin-induced cell apoptosis whereas anti-miR-301a enhanced apoptosis in OS cells, suggesting that up-regulation of miR-301a contributed to chemoresistance of OS cells. Consistently, our data showed that miR-301a and HMGCR were up-regulated in chemotherapy-resistant OS compared to those in control OS. Our findings suggested that miR-301a might be a potential biomarker for chemotherapy-resistant OS and a promising therapeutic target for overcoming drug resistance of OS.
Righi A, Gambarotti M, Longo S, et al. Small cell osteosarcoma: clinicopathologic, immunohistochemical, and molecular analysis of 36 cases. Am J Surg Pathol. 2015; 39(5):691-9 [PubMed] Related Publications
Small round cell osteosarcoma is a very rare type of osteosarcoma, histologically mimicking other small round cell malignancies of bone, most notably Ewing sarcoma. To distinguish small cell osteosarcoma from other primary small cell malignancies of bone, we evaluated the immunohistochemical (IHC) expression of CD99 and SATB2, a marker of osteoblastic differentiation. Second, we analyzed EWSR1 and FUS gene aberrations using fluorescence in situ hybridization and/or reverse transcription-polymerase chain reaction (RT-PCR) techniques to assess whether small cell osteosarcoma and Ewing sarcoma share the same genetic alteration analysis. Thirty-six cases of primitive small cell osteosarcoma of bone were included in this study. All the cases of small cell osteosarcoma showed strong nuclear expression of SATB2 associated with negativity for CD99 antibody or weak, cytoplasmic staining in few neoplastic cells. Reverse transcription-polymerase chain reaction was negative for EWS-FLI1 type 1-2, EWS-ERG type 1, and CIC-DUX4 in the 10 available cases of small cell osteosarcoma analyzed. Fluorescence in situ hybridization analysis was feasible with a readable signal in 13 cases of small cell osteosarcoma, and none of these cases showed any EWSR1 and FUS gene rearrangements. In conclusion, it appears extremely useful to combine IHC analysis of SATB2 and CD99 with molecular analysis of Ewing sarcoma-associated genetic aberrations, to differentiate small cell osteosarcoma from other small round cell malignancies of bone. The strong IHC expression of SATB2 associated with CD99 immunonegativity and the absence of EWSR1 and FUS gene rearrangements in small cell osteosarcoma argues against the existence of a morphologic/genetic continuum with Ewing sarcoma.