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Bone Cancers

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.

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Chondrosarcoma
Ewing's Sarcoma
Osteosarcoma
Primary Lymphoma of Bone
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Adiguzel M, Horozoglu C, Kilicoglu O, et al.
MMP-3 gene polymorphisms and Osteosarcoma.
Indian J Exp Biol. 2016; 54(3):175-9 [PubMed] Related Publications
Osteosarcoma (OSA) is the most common adolescence cancer among all primary bone tumors next only to multiplemyeloma. It has a substantially worse prognosis and ability to metastasize to lung. MMPs (matrix metalloproteinases) are among the major proteases that take part in regulation of ECM (extracellular matrix). MMPs play an active role in the formation of the osteoid tissue, rich in collagens and other ECM proteoglycans. They also take part in pro-osteoclast, osteoclast, osteoblast, and osteoid formation. Many members of the MMP gene family have been linked to human cancers. It has been shown that MMPs particularly play a role in the tumor's acquisition of an invasive and metastatic character. In our study, the E45K and T102T polymorphisms of MMP-3 were studied using the PCR-RFLP method in 135 Turkish subjects (54 subjects with osteosarcoma and 81 healthy controls). We found that frequencies of E45K G allele (p:0,010, χ²:6,710, OR:1,429, 95% Cl: 1,019-1,858) and AG genotype (p:0,001, χ²:14,753, OR:2,32, 95% Cl: 1,491-3,626) were elevated in patients compared to controls. Besides, there was a significant difference in.E45K AA genotype between study groups (p:0,004, χ²:8,182, OR: 2,929, 95% Cl: 1,38-6,19). There were no significant differences between any genotypes or allele in the control and patient groups for MMP-3 T102T polymorphism. Our findings indicate that the G allele and AG genotype of MMP-3 E45K polymorphism is associated with increased risk of osteosarcoma in adolescent population of Turkey.

Song J, Wang X, Zhu J, Liu J
Rapamycin causes growth arrest and inhibition of invasion in human chondrosarcoma cells.
J BUON. 2016 Jan-Feb; 21(1):244-51 [PubMed] Related Publications
PURPOSE: Chondrosarcoma is a highly malignant tumor that is characterized by a potent capacity to invade locally and cause distant metastasis and notable for its lack of response to conventional chemotherapy or radiotherapy. Rapamycin, the inhibitor of mammalian target of rapamycin (mTOR), is a valuable drug with diverse clinical applications and regulates many cellular processes. However, the effects of rapamycin on cell growth and invasion of human chondrosarcoma cells are not well known.
METHODS: We determined the effect of rapamycin on cell proliferation, cell cycle arrest and invasion by using MTS, flow cytometry and invasion assays in two human chondrosarcoma cell lines, SW1353 and JJ012. Cell cycle regulatory and invasion-related genes' expression analysis was performed by quantitative RT-PCR (qRT-PCR). We also evaluated the effect of rapamycin on tumor growth by using mice xenograph models.
RESULTS: Rapamycin significantly inhibited the cell proliferation, induced cell cycle arrest and decreased the invasion ability of human chondrosarcoma cells. Meanwhile, rapamycin modulated the cell cycle regulatory and invasion-related genes' expression. Furthermore, the tumor growth of mice xenograph models with human chondrosarcoma cells was significantly inhibited by rapamycin.
CONCLUSIONS: These results provided further insight into the role of rapamycin in chondrosarcoma. Therefore, rapamycin targeted therapy may be a potential treatment strategy for chondrosarcoma.

Huang JF, Du WX, Chen JJ
Elevated expression of matrix metalloproteinase-3 in human osteosarcoma and its association with tumor metastasis.
J BUON. 2016 Jan-Feb; 21(1):235-43 [PubMed] Related Publications
PURPOSE: Matrix metalloproteinase-3 (MMP-3) is one of the several MMPs that is associated with malignant tumors of breast, colon, cervix and lung, where its expression has been correlated with tumor invasion and metastasis. However, the role of MMP-3 in metastasis of osteosarcoma has not yet been explored.
METHODS: MMP-3 expression in 15 primary and metastatic osteosarcomas with case-matched adjacent non-tumor tissue was assessed by immunohistochemistry and quantitative RT-PCR. Further, MMP-3 mRNA and protein levels were also determined in osteoblast and osteosarcoma cell lines. Additionally, migration and invasion assays were performed in MMP-3 knockdown cells.
RESULTS: MMP-3 was expressed in 86.6% (13/15) of the osteosarcoma patients and its expression was significantly higher in metastatic tumors as compared to the primary osteosarcoma tumor tissues. Furthermore, osteosarcoma cell lines showed higher MMP-3 expression as compared to osteoblast cell lines. siRNA mediated MMP-3 knockdown in osteosarcoma cell lines significantly inhibited their migration and invasion properties.
CONCLUSION: Our results demonstrated that MMP-3 expression is deregulated in osteosarcomas and this potentially contributes to metastasis and might be a promising marker for the prognosis and therapy of metastatic osteosarcoma.

Avril P, Duteille F, Ridel P, et al.
Opposite Effects of Soluble Factors Secreted by Adipose Tissue on Proliferating and Quiescent Osteosarcoma Cells.
Plast Reconstr Surg. 2016; 137(3):865-75 [PubMed] Related Publications
BACKGROUND: Autologous adipose tissue transfer may be performed for aesthetic needs following resection of osteosarcoma, the most frequent primary malignant tumor of bone, excluding myeloma. The safety of autologous adipose tissue transfer regarding the potential risk of cancer recurrence must be addressed.
METHODS: Adipose tissue injection was tested in a human osteosarcoma preclinical model induced by MNNG-HOS cells. Culture media without growth factors from fetal bovine serum were conditioned with adipose tissue samples and added to two osteosarcoma cell lines (MNNG-HOS and MG-63) that were cultured in monolayer or maintained in nonadherent spheres, favoring a proliferation or quiescent stage, respectively. Proliferation and cell cycle were analyzed.
RESULTS: Adipose tissue injection increased local growth of osteosarcoma in mice but was not associated with aggravation of lung metastasis or osteolysis. Adipose tissue-derived soluble factors increased the in vitro proliferation of osteosarcoma cells up to 180 percent. Interleukin-6 and leptin were measured in higher concentrations in adipose tissue-conditioned medium than in osteosarcoma cell-conditioned medium, but the authors' results indicated that they were not implicated alone. Furthermore, adipose tissue-derived soluble factors did not favor a G0-to-G1 phase transition of MNNG-HOS cells in nonadherent oncospheres.
CONCLUSIONS: This study indicates that adipose tissue-soluble factors activate osteosarcoma cell cycle from G1 to mitosis phases, but do not promote the transition from quiescent G0 to G1 phases. Autologous adipose tissue transfer may not be involved in the activation of dormant tumor cells or cancer stem cells.

Dierselhuis EF, Gerbers JG, Ploegmakers JJ, et al.
Local Treatment with Adjuvant Therapy for Central Atypical Cartilaginous Tumors in the Long Bones: Analysis of Outcome and Complications in One Hundred and Eight Patients with a Minimum Follow-up of Two Years.
J Bone Joint Surg Am. 2016; 98(4):303-13 [PubMed] Related Publications
BACKGROUND: A central atypical cartilaginous tumor (ACT)--formerly known as chondrosarcoma grade 1 (CS1)--is a tumor of intermediate-type malignancy, often treated with surgery. The extent of surgery remains controversial, as some advocate resection and others favor local treatment by curettage. Because of the low prevalence of ACT/CS1, the available data are limited and generally not uniform. The purpose of this study was to present the outcome for a large cohort of patients with ACT/CS1 in the long bones who were treated with curettage and adjuvant phenolization and followed for a minimum of two years according to national guidelines.
METHODS: A retrospective study was designed to analyze data from 108 patients treated for central ACT/CS1 in the long bones between 2006 and 2012. All patients were treated with curettage and adjuvant phenolization, and defects were filled with polymethylmethacrylate, bone graft, or bone substitutes. The primary end point was local recurrence or residual tumor. Secondary end points included the type and rate of complications and reoperations.
RESULTS: All patients were free from local recurrence at a mean follow-up of 48.7 months (range, 24.3 to 97.5 months). Residual tumor was suspected in five patients, leading to a 95.4% disease-free survival rate. A fracture occurred in eleven patients (10.2%). Other complications were osseous penetration during the surgery (two patients), wound infection (one patient), arthrofibrosis (one patient), and skin necrosis (one patient). Tumor volume was related neither to the risk of fracture nor to the occurrence of residual tumor.
CONCLUSIONS: In our experience, curettage of ACT/CS1 in the long bones with adjuvant phenolization is safe, even with large tumors of up to 100 cm(3). Most worrisome is the risk of fracture, which occurred in 10.2% of our patients. Considering the relatively mild behavior of ACT/CS1, less aggressive treatment, by observation or by minimally invasive surgery, could be the next step that should be evaluated prospectively.

Yoshiyama A, Morii T, Ohtsuka K, et al.
Development of Stemness in Cancer Cell Lines Resistant to the Anticancer Effects of Zoledronic Acid.
Anticancer Res. 2016; 36(2):625-31 [PubMed] Related Publications
BACKGROUND: Drug resistance is closely related to cancer cell stemness, that is acquired along with resistance to various anticancer agents. However, this has not been investigated as a potential mechanism underlying cancer cell resistance to zoledronate, that is used to suppress bone metastasis.
MATERIALS AND METHODS: Zoledronate-resistant A549 lung cancer and MG63 osteosarcoma cell lines were established by repeated treatment with sub-lethal concentrations of zoledronate. Expression levels of the stem cell marker NANOG, cMYC, octamer-binding transcription factor 4, and sex-determining region Y-box 2 were evaluated and sphere formation was compared between parental and resistant cell lines. Tumourigenicity was assessed in vivo.
RESULTS: Stem cell marker expression was up-regulated and sphere formation was enhanced in resistant compared to parental cells and showed greater tumour formation capacity in mice.
CONCLUSION: Repeated treatment of malignant tumour cell lines with zoledronate, induces the development of drug resistance and stemness.

Hao L, Liao Q, Tang Q, et al.
Id-1 promotes osteosarcoma cell growth and inhibits cell apoptosis via PI3K/AKT signaling pathway.
Biochem Biophys Res Commun. 2016; 470(3):643-9 [PubMed] Related Publications
Accumulating evidence reveals that Id-1 is upregulated and functions as a potential tumor promoter in several human cancer types. However, the role of Id-1 in osteosarcoma (OS) is unknown. In present study, we found that Id-1 expression was elevated in OS tissues than adjacent normal bone tissues. More importantly, we demonstrated that overexpression of Id-1 is significantly correlated with tumor progression and poor survival in OS patients. Furthermore, increased expression of Id-1 was observed in OS cell lines and ectopic expression of Id-1 significantly enhanced in vitro cell proliferation and promoted in vivo tumor growth, whereas knockdown of Id-1 suppressed OS cells growth. Moreover, our experimental data revealed that Id-1 promotes cell proliferation by facilitating cell cycle progression and inhibits cell apoptosis. Mechanistically, the effects of Id-1 in OS cells is at least partly through activation of PI3K/Akt signaling pathway. Therefore, we identified a tumorigenic role of Id-1 in OS and suggested a potential therapeutic target for OS patients.

Wu Q, Paul A, Su D, et al.
Structure of BRCA1-BRCT/Abraxas Complex Reveals Phosphorylation-Dependent BRCT Dimerization at DNA Damage Sites.
Mol Cell. 2016; 61(3):434-48 [PubMed] Free Access to Full Article Related Publications
BRCA1 accumulation at DNA damage sites is an important step for its function in the DNA damage response and in DNA repair. BRCA1-BRCT domains bind to proteins containing the phosphorylated serine-proline-x-phenylalanine (pSPxF) motif including Abraxas, Bach1/FancJ, and CtIP. In this study, we demonstrate that ionizing radiation (IR)-induces ATM-dependent phosphorylation of serine 404 (S404) next to the pSPxF motif. Crystal structures of BRCT/Abraxas show that phosphorylation of S404 is important for extensive interactions through the N-terminal sequence outside the pSPxF motif and leads to formation of a stable dimer. Mutation of S404 leads to deficiency in BRCA1 accumulation at DNA damage sites and cellular sensitivity to IR. In addition, two germline mutations of BRCA1 are found to disrupt the dimer interface and dimer formation. Thus, we demonstrate a mechanism involving IR-induced phosphorylation and dimerization of the BRCT/Abraxas complex for regulating Abraxas-mediated recruitment of BRCA1 in response to IR.

Mazari PM, Weber KL, Kim S, Zhang PJ
Cytogenetically confirmed low-grade fibromyxoid sarcoma arising from the tibia.
Hum Pathol. 2016; 48:56-9 [PubMed] Related Publications
Low-grade fibromyxoid sarcoma is a rare soft tissue tumor with a benign histologic appearance but comparatively aggressive clinical course. These discrepant features make it extremely important to diagnose early so that appropriate management can be initiated. This diagnosis often hinges on the presence of the hallmark cytogenetic aberration, a balanced 7;16 translocation resulting in a FUS-CREB3L2 fusion gene. Although this neoplasm most commonly arises in the deep soft tissue of the lower extremities, it has been reported to arise from a wide variety of sites including intraabdominal and intracranial locations. Only 1 previous study has described low-grade fibromyxoid sarcoma as arising from a bony site; however, cytogenetic and immunohistochemical confirmation was not available at that time. Herein, we describe the first ever cytogenetically confirmed case of low-grade fibromyxoid sarcoma arising as a primary bone tumor in the tibia of a 35-year-old woman.

van Maldegem AM, Bovée JV, Peterse EF, et al.
Ewing sarcoma: The clinical relevance of the insulin-like growth factor 1 and the poly-ADP-ribose-polymerase pathway.
Eur J Cancer. 2016; 53:171-80 [PubMed] Related Publications
BACKGROUND: In the last three decades the outcome for patients with localised Ewing sarcoma (ES) has improved significantly since the introduction of multimodality primary treatment. However, for patients with (extra-) pulmonary metastatic and/or non-resectable relapsed disease the outcome remains poor and new treatment options are urgently needed. Currently the insulin-like growth factor 1 receptor (IGF-1R) pathway and the poly-ADP(adenosinediphosphate)-ribose-polymerase (PARP) pathway are being investigated for potential targeted therapies. IGF-1R: The IGF-1R pathway is known to be deregulated by the EWSR1-FLI1 translocation which makes it a potential target for therapy. Clinical trials have been reported in which only ES patients were treated with an IGF-1R inhibitor, either as single agent or in combination. In total 291 ES patients were included in these trials, in which two (0.7%) complete responses, 32 (11%) partial responses of which some durable, and 61 (21%) stable diseases were observed. PARP: In the presence of a PARP inhibitor DNA strand breaks cannot be efficiently repaired, leading to cell death. The first phase II trial with ES patients was recently published and showed no clinical responses, which may have been due to the drug being non-effective as a single agent.
DISCUSSION: The IGF-1R pathway is an interesting target for ES and should be explored further, as biomarkers to select patients that might benefit from treatment are lacking. PARP inhibitors as single agent have so far failed to show improvement in outcome. Future directions include dual insulin receptor/IGF-1R blockade with linsitinib as well as chemotherapy-PARP combinations. Both therapeutic strategies are currently being explored.

Tang C, Ao PY, Zhao YQ, et al.
Effect and mechanism of dihydroartemisinin on proliferation, metastasis and apoptosis of human osteosarcoma cells.
J Biol Regul Homeost Agents. 2015 Oct-Dec; 29(4):881-7 [PubMed] Related Publications
Osteosarcoma represents an aggressive type of bone malignancy that poses a significant health threat. The objective of the current study was to analyze the effect and mechanism of dihydroartemisinin (DHA) on the proliferation, metastasis and apoptosis of human osteosarcoma cells. A gradient concentration of DHA (15, 25 and 35 μmol.L-1) was used to stimulate the cells, along with control and Dimethyl sulfoxide (DMSO). The phenotypic outcomes were characterized using MTT assay, clone formation assay, Hoechst 33258 staining assay, luciferase reporter plasmid assay, Western blot and wound healing assay. In addition, IBM SPSS Statistics 18.0 software was applied for statistical analysis and all experimental data were expressed as mean ± s.d. Analysis of variance (ANOVA) was applied to compare the differences among multiple groups. Our results demonstrated that DHA inhibited the proliferation and metastasis of osteosarcoma cells and promoted the apoptosis in the cytomorphosis.

Kimura Y, Sumiyoshi M, Baba K
Antitumor and Antimetastatic Activity of Synthetic Hydroxystilbenes Through Inhibition of Lymphangiogenesis and M2 Macrophage Differentiation of Tumor-associated Macrophages.
Anticancer Res. 2016; 36(1):137-48 [PubMed] Related Publications
An increase in tumor-associated macrophages (TAMs) around the tumor microenvironment has been closely associated with a poor prognosis in patients with cancer, and M2 TAMs promote tumor growth and tumor metastasis by stimulating angiogenesis or lymphangiogenesis in tumors. We herein examined the effects of nine synthetic hydroxystilbenes on M2 macrophage activation and differentiation, and three selected dihydroxystilbenes on vascular endothelial cell growth factor (VEGF)-C-induced tube formation in human lymphatic endothelial cells (HLECs) (in vitro). We also investigated the antitumor and antimetastatic effects of three synthetic dihydroxystilbenes in LM8-bearing mice in vivo. The three selected synthetic stilbenes (at concentrations of 5, 10, 25, and 50 μM) inhibited the production of interleukin-10 and monocyte chemoattractant protein-1 in M2 macrophages, but promoted that of transforming growth factor-β1. The three dihydroxystilbenes (at concentrations of 10-50 μM) inhibited the phosphorylation of signal transducer and activator of transcript 3 without affecting its expression in the differentiation of M2 macrophages. Furthermore, the 2,3- and 4,4'-dihydroxystilbene inhibited VEGF-C-induced lymphangiogenesis in HLECs. Both 2,3- and 4,4'-dihydroxystilbene (at 10 and 25 mg/kg, twice daily) inhibited tumor growth and metastasis to the lung in mice. These results suggested that the antitumor and antimetastatic effects of 2,3- and 4,4'-dihydroxystilbene were partly due to anti-lymphangiogenesis, and the regulation of M2 macrophage activation and differentiation.

Fauske L, Lorem G, Grov EK, Bondevik H
Changes in the body image of bone sarcoma survivors following surgical treatment--A qualitative study.
J Surg Oncol. 2016; 113(2):229-34 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AND OBJECTIVES: Among several long-term effects, people treated for cancer may experience an altered appearance. Our study aims to identify how visible body changes following surgical treatment affect the life and identity of primary bone sarcoma survivors 3-10 years after diagnosis. A qualitative, phenomenological, and hermeneutic design was applied.
METHODS: Sarcoma survivors (n = 18) who were previously treated at Norwegian Radium Hospital, Oslo University Hospital, participated in the study. In-depth and semi-structured interviews were conducted and analyzed using inductive thematic analysis.
RESULTS: The main finding of this study concerned how altered appearance after bone cancer treatment in the hip/pelvis or lower extremities affected the participants' self-esteem. Half of the participants expressed concerns about their visible differences, particularly those with functional impairment. They felt that it is important to hide the bodily signs of changes to appear as normal as possible, as well as attractive and healthy. They describe, with specific examples, how these changes influence their self-realization, especially their social life.
CONCLUSIONS: Healthcare providers who guide bone sarcoma survivors during follow-up should develop a comprehensive understanding of what it means to cope with a changed and challenging body.

Yang G, Zhang P, Lv A, et al.
MiR-205 functions as a tumor suppressor via targeting TGF-α in osteosarcoma.
Exp Mol Pathol. 2016; 100(1):160-6 [PubMed] Related Publications
Osteosarcoma (OS) is the most common primary bone cancer, and it is most prevalent in children and young adults. The prognosis of OS remains poor, and survival of OS reached a plateau. The discovery of microRNAs (miRNAs) provides a new possibility for the early diagnosis and treatment of OS. In this study, we detected the expression level of miR-205 and Transforming growth factor-alpha (TGF-α) in 15 cases of clinical OS tissues and adjacent normal bone tissues. We found that the expression of miR-205 was significantly lower in OS tissues than in normal bone tissues; the expression of TGF-α mRNA was significantly increased in OS tissues than in normal bone tissues, the miR-205 was negatively correlated with TGF-α levels in both OS and normal bone tissues. Functional studies demonstrated that miR-205 significantly decreased the capability of cell proliferation, invasion and migration and induced G0/G1 growth arrest and apoptosis in OS cells. By using bioinformatics analytic tool (Targetscan), the 3'UTR of TGF-α gene was found to be a target of miR-205. Luciferase report assay further confirmed that TGF-α 3'UTR is a direct target of miR-205. We also found that the expression of TGF-α mRNA and protein was significantly down-regulated or up-regulated after miR-205 mimic or miR-205 inhibitor transfection. TGF-α knockdown study further showed that miR-205 regulated cell proliferation, invasion and migration by targeting TGF-α in OS. Enforced expression of TGF-α sufficiently restore the effects of miR-205 on cell proliferation, invasion and migration. In conclusion, our study suggested that miR-205 may function as a tumor suppressor via targeting TGF-α in OS, and the abnormal expression of miR-205 might be a key factor in OS progression.

Ye S, Shen J, Choy E, et al.
p53 overexpression increases chemosensitivity in multidrug-resistant osteosarcoma cell lines.
Cancer Chemother Pharmacol. 2016; 77(2):349-56 [PubMed] Article available free on PMC after 01/02/2017 Related Publications
PURPOSE: Multidrug resistance (MDR) is a major obstacle to the successful treatment of osteosarcoma with chemotherapy. Effectiveness of cancer therapy correlates with the ability to induce a p53-dependent apoptotic response. p53 is a tumor suppressor gene that is mutated in 22 % of osteosarcomas. While impaired p53 has been implicated in the oncogenesis of osteosarcoma, it is unclear whether overexpression of wild-type p53 can increase chemosensitivity in MDR osteosarcoma cells.
METHODS: We transfected a plasmid encoding the wild-type p53 gene to MDR osteosarcoma cell lines, which have different p53 statuses, U-2OSR2 with wild-type p53 (Wt-p53) and KHOSR2 with mutant p53 (Mt-p53), and determined the effect of p53 overexpression on chemosensitivities.
RESULTS: Both of the U-2OSR2 and KHOSR2 cell lines displayed similar trends in p53-induced drug sensitivities. However, it seems that the impact of p53 overexpression is different based on the differential intrinsic p53 status in these cell lines. In the KHOSR2 cell line (Mt-p53), overexpression of p53 up-regulates the expression of pro-apoptotic protein p21 and Bax, while in the U-2OSR2 cell line (Wt-p53), overexpression of p53 down-regulates IGF-1r expression significantly.
CONCLUSIONS: These results demonstrated that transfection of wild-type p53 increases chemosensitivity either through inhibiting IGF-1r or through increasing the expression of pro-apoptotic proteins p21 and Bax in human MDR osteosarcoma cell lines.

Zhang Y, Ding C, Wang J, et al.
Prognostic significance of CD44V6 expression in osteosarcoma: a meta-analysis.
J Orthop Surg Res. 2015; 10:187 [PubMed] Article available free on PMC after 01/02/2017 Related Publications
Numerous individual studies evaluating the relationship between CD44V6 over-expression and prognostic impact in patients with osteosarcoma (OS) have yielded in conclusive results. This meta-analysis aimed to determine the value of cell adhesion molecule CD44V6 in prognosis of OS by conducting a systematic review and meta-analysis. A comprehensive search was conducted using PubMed (medline), Embase, ISI Web of Knowledge, Springer, the Cochrane Library, Scopus, BioMed Central, ScienceDirect, Wanfang, Weipu, and China National Knowledge Internet (CNKI) databases from inception through May 26, 2015. All available articles written in English or Chinese that investigated the expression of CD44V6 and the prognosis of OS were included. The quantity of the studies was evaluated according to the critical review checklist of the Dutch Cochrane Centre proposed by MOOSE. Finally, a total of eight studies with 486 OS patients were involved and the results indicated that the positive expression of CD44V6 predicts neoplasm metastasis (RR = 1.76, 95 % CI 1.38-2.25, p < 0.00001), and poor survival in OS with the pooled HR of 1.53 (95 % CI 1.25-1.88, p < 0.0001). No significant heterogeneity was observed among all studies. In conclusion, the present meta-analysis and systematic review strongly suggest that CD44V6 over-expression is associated with overall survival rate and metastasis in OS, and may be used as a prognostic biomarker to guide the clinical therapy for OS.

Yoshida A, Goto K, Kodaira M, et al.
CIC-rearranged Sarcomas: A Study of 20 Cases and Comparisons With Ewing Sarcomas.
Am J Surg Pathol. 2016; 40(3):313-23 [PubMed] Related Publications
The CIC gene rearrangement exists in a subset of small round cell sarcomas. As the nosologic relationship of these sarcomas to Ewing sarcomas remains undetermined, we examined 20 CIC-rearranged sarcomas to compare their clinicopathologic features with those of Ewing sarcomas. The CIC-rearranged sarcomas were from a group of 14 men and 6 women with a median age of 24.5 years. The primary tumor sites included the limbs, trunk wall, internal trunk, lung, cerebrum, and pharynx. A comparison of the demographic and clinical characteristics of the 20 patients with CIC-rearranged sarcomas with those of the 53 near-consecutive patients with EWSR1-rarranged Ewing sarcomas showed that there were no differences with respect to their ages and sexes. Although none of the CIC-rearranged sarcomas arose in the bone, 40% of the Ewing sarcomas primarily affected the skeleton. The overall survival of patients with Ewing sarcomas was significantly better than that for patients with CIC-rearranged sarcomas. A histologic comparison of the CIC-rearranged sarcomas with 20 EWSR1-rearranged Ewing sarcomas showed significantly higher degrees of lobulation, nuclear pleomorphism, the prominence of the nucleoli, spindle cell elements, and myxoid changes in the CIC-rearranged sarcomas. Distinguishing immunohistochemical features included heterogenous CD99 reactivity, nuclear WT1 expression, and calretinin expression in the CIC-rearranged sarcomas and NKX2.2 expression in the Ewing sarcomas. CIC-rearranged sarcomas are distinct from Ewing sarcomas clinically, morphologically, and immunohistochemically, and they should be considered a separate entity rather than being grouped within the same family of tumors.

Ben-Ami T, Waldman E, Marc W, et al.
Ewing Sarcoma: A 15-Year Experience of a Single Center With the MSKCC P6 Treatment Protocol.
J Pediatr Hematol Oncol. 2016; 38(1):38-42 [PubMed] Related Publications
INTRODUCTION: Ewing sarcoma (ES) is the second most common bone tumor in children. Current chemotherapeutic regimens include high-dose anthracyclines and alkylating agents with significant variation in treatment length. The Memorial Sloan Kettering Cancer Center P6 regimen (MSKCC P6) treatment protocol is a highly aggressive regimen given over 21 weeks only. We present the outcome of ES patients treated in our center with this protocol over the last 15 years.
PROCEDURE: We retrospectively analyzed data on the presentation, patient characteristics, treatment, and outcome of all ES patients treated according to the MSKCC P6 regimen from 1999 to 2014.
RESULTS: Of 48 patients, 37 (77%) presented with a nonmetastatic disease and 26 (54%) with tumor located in the extremities. The 5-year overall survival (OS) of the entire cohort was 55.9% ± 8%. Nonmetastatic disease conferred a better prognosis with a 5-year OS of 68.4% ± 8.5%. Patients with a nonmetastatic extremity tumor had the most favorable outcome with 5-year OS of 72.2% ± 9.8%.
CONCLUSION: The outcome of ES patients after a short aggressive course of chemotherapy (the MSKCC P6 protocol), is comparable to that following other first-line treatment regimens in use, with potentially fewer long-term adverse events.

Nugent M
microRNA and Bone Cancer.
Adv Exp Med Biol. 2015; 889:201-30 [PubMed] Related Publications
MicroRNA molecules have a variety of roles in cellular development and proliferation processes, including normal osteogenesis. These effects are exerted through post-translational inhibition of target genes. Altered miRNA expression has been demonstrated in several cancers, both in the tumor tissue and in the peripheral circulation. This may influence carcinogenesis if the specific miRNA targets are encoded by tumor suppressor genes or oncogenes. To date, most research investigating the role of microRNAs and primary bone tumors has focused on osteosarcoma and Ewing sarcoma. Several microRNAs including the miR-34 family have been implicated in osteosarcoma tumorigenesis via effects on the Notch signaling pathway. Progression, invasion, and metastasis of osteosarcoma tumor cells is also influenced by microRNA expression. In addition, microRNA expression may affect the response to chemotherapy in osteosarcoma and thus hold potential for future use as either a prognostic indicator or a therapeutic target. The EWS-FLI1 fusion protein produced in Ewing sarcoma has been shown to induce changes in miRNA expression. MicroRNA expression profiling may have some potential for prediction of disease progression and survival in Ewing sarcoma. There is limited evidence to support a role for microRNAs in other primary bone tumors, either malignant or benign; however, early work is suggestive of involvement in chondrosarcoma, multiple osteochondromatosis, and giant cell tumors of bone.

Laitinen M, Parry M, Albergo JI, et al.
The prognostic and therapeutic factors which influence the oncological outcome of parosteal osteosarcoma.
Bone Joint J. 2015; 97-B(12):1698-703 [PubMed] Related Publications
The aim of this study was to evaluate the prognostic and therapeutic factors which influence the oncological outcome of parosteal osteosarcoma. A total of 80 patients with a primary parosteal osteosarcoma were included in this retrospective study. There were 51 females and 29 males with a mean age of 29.9 years (11 to 78). The mean follow-up was 11.2 years (1 to 40). Overall survival was 91.8% at five years and 87.8% at ten years. Local recurrence occurred in 14 (17.5%) patients and was associated with intralesional surgery and a large volume of tumour. On histological examination, 80% of the local recurrences were dedifferentiated high-grade tumours. A total of 12 (14.8%) patients developed pulmonary metastases, of whom half had either a dedifferentiated tumour or a local recurrence. Female gender and young age were good prognostic factors. Local recurrence was a poor prognostic factor for survival. Medullary involvement or the use of chemotherapy had no impact on survival. The main goal in treating a parosteal osteosarcoma must be to achieve a wide surgical margin, as inadequate margins are associated with local recurrence. Local recurrence has a significant negative effect on survival, as 80% of the local recurrences are high-grade dedifferentiated tumours, and half of these patients develop metastases. The role of chemotherapy in the treatment of parosteal osteosarcoma is not as obvious as it is in the treatment of conventional osteosarcoma. The mainstay of treatment is wide local excision.

Anderson ME
Update on Survival in Osteosarcoma.
Orthop Clin North Am. 2016; 47(1):283-92 [PubMed] Related Publications
Osteosarcoma is the most common primary bone malignancy in children. Treatment has evolved to include systemic chemotherapy and local control surgery. Although survival improved initially in a drastic fashion with this approach, recent decades have seen little to no further gains in this area. Limb salvage surgery evolved with effective chemotherapy and advances in imaging, and continues to improve in the recent era. This article serves as a review of survival in high-grade osteosarcoma: prognostic factors, advances in chemotherapy and surgery, late effects of chemotherapy and surgery in survivors, and future directions.

Zhou X, Shi X, Ren K, et al.
Celecoxib inhibits cell growth and modulates the expression of matrix metalloproteinases in human osteosarcoma MG-63 cell line.
Eur Rev Med Pharmacol Sci. 2015; 19(21):4087-97 [PubMed] Related Publications
OBJECTIVE: The goal of this study was to determine the effect of celecoxib, a selective COX-2 inhibitor, on the growth inhibition of osteosarcoma and its potential anticancer mechanisms.
MATERIALS AND METHODS: Human osteosarcoma cell line MG-63 was used as a model. The inhibitory effect of celecoxib on cell proliferation was assessed by MTT assay. Flow cytometric analysis was used to detect the effects of celecoxib on cell cycle and apoptosis. Western blot analysis was used to detect the protein expression of RECK, matrix metalloproteinase (MMP)-2 and MMP-9 in celecoxib-treated MG-63 cells.
RESULTS: MTT assays showed that at a range of concentrations (0-80 µg/ml), celecoxib significantly inhibited the MG-63 cell proliferation in a time- and concentration-dependent manner. The half maximal inhibitory concentration (IC50) of celecoxib was 47.5 µg/ml for 24 h-treatment and 19.2 µg/ml for 48 h-treatment. Flow cytometric analysis demonstrated that treatment with 20 µg/ml celecoxib led to a significant cell cycle arrest at S-phase and an enhancement of apoptosis induction in MG-63 cells at 24 or 48h. Moreover, compared with 24 h-treatment, 48 h-treatment induced more S-phase arrest and apoptosis in MG-63 cells. Western blot analyses revealed that the expression of MMP-2 and MMP-9 was markedly down-regulated but RECK, an inhibitor of MMPs, was markedly up-regulated in MG-63 cells exposed to 20 µg/ml celecoxib for 24 or 48h. Furthermore, the effects of celecoxib on the expression of these molecules were more evident with the increase of treatment time.
CONCLUSIONS: Celecoxib inhibits the MG-63 cells proliferation through S-phase arrest and apoptosis induction. Celecoxib-induced down-regulation of MMP-2 and MMP-9 and up-regulation of RECK may contribute to the apoptosis induction and an alteration in local tumor microenvironment. These findings suggest that celecoxib may exert at least in part of its anticancer effects via up-regulation of RECK to inhibit the expression of MMP-2 and MMP-9.

Edelmann MN, Daryani VM, Bishop MW, et al.
Neurocognitive and Patient-Reported Outcomes in Adult Survivors of Childhood Osteosarcoma.
JAMA Oncol. 2016; 2(2):201-8 [PubMed] Article available free on PMC after 01/02/2017 Related Publications
IMPORTANCE: This study provides the first objective data documenting neurocognitive impairment in long-term survivors of childhood osteosarcoma.
OBJECTIVE: To examine neurocognitive, neurobehavioral, emotional, and quality-of-life outcomes in long-term survivors of childhood osteosarcoma.
DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional cohort study at an academic research hospital, with prospective treatment and chronic health predictors. Outcome data were collected from June 2008 to August 2014. Data analysis was completed in April 2015. Survivors of osteosarcoma recruited from the St Jude Lifetime Cohort Study were compared with community controls.
MAIN OUTCOMES AND MEASURES: Neurocognitive function, neurobehavioral symptoms, emotional distress, and quality of life. Outcomes were examined in relation to pharmacokinetic indices of methotrexate exposure and current chronic health conditions, which were assessed through medical examination and coded according to Common Terminology Criteria for Adverse Events, Version 4.03.
RESULTS: Eighty survivors of osteosarcoma (mean [SD] age, 38.9 [7.6] years; time since diagnosis, 24.7 [6.6] years; 42% female) were compared with 39 community controls (age, 39.0 [11.7] years; 56% female). Survivors demonstrated lower mean scores in reading skills (-0.21 [95% CI, -0.32 to -0.10] vs 0.05 [95% CI, -0.13 to 0.23]; P = .01), attention (-0.78 [95% CI, -1.32 to -0.24] vs 0.24 [95% CI, -0.07 to 0.55]; P = .002), memory (-0.24 [95% CI, -0.48 to 0] vs 0.27 [95% CI, -0.08 to 0.62]; P = .01), and processing speed (-0.15 [95% CI, -0.35 to 0.05] vs 0.74 [95% CI, 0.44 to 1.03]; P < .001). Results of pharmacokinetic analysis showed that high-dose methotrexate maximum plasma concentration (estimate = 0; P = .48), median clearance (estimate = -0.11; P = .76), and median/cumulative exposure (estimate = 0; P = .45) were not associated with neurocognitive outcomes. Any grade 3 or 4 Common Terminology Criteria for Adverse Events cardiac, pulmonary, or endocrine condition was associated with poorer memory (t = 2.93; P = .006) and slower processing speed (t = 3.03; P = .002). Survivor-reported poor general health was associated with decreased sustained attention (estimate = 0.24; P = .05) and processing speed (estimate = 0.34; P = .005).
CONCLUSIONS AND RELEVANCE: Long-term survivors of osteosarcoma are at risk for neurocognitive impairment, which is related to current chronic health conditions and not to original treatment with high-dose methotrexate. Prospective longitudinal studies are needed to identify onset and progression of impairment to inform optimal interventions.

Yang L, Liu ZM, Rao YW, et al.
Downregulation of microRNA-586 Inhibits Proliferation, Invasion and Metastasis and Promotes Apoptosis in Human Osteosarcoma U2-OS Cell Line.
Cytogenet Genome Res. 2015; 146(4):268-78 [PubMed] Related Publications
In this study, we aim to examine the association of microRNA-586 (miR-586) with osteosarcoma (OS) cell proliferation, apoptosis, invasion, and metastasis. U2-OS cell lines were divided into 4 groups: an miR-586 group, anti-miR-586 group, control group (empty plasmid) and blank group (no plasmid). qRT-PCR was used to detect miR-586 expression, cell counting kit-8 and EdU assays to detect cell proliferation, flow cytometry to detect cell cycle distribution, Annexin V/PI double staining to detect cell apoptosis, and the Transwell assay to detect cell invasion and metastasis. miR-586 expression was significantly higher in the miR-586 group but significantly lower in the anti-miR-586 group compared with the control and blank groups. Cell proliferation at 2-5 days after cell transfection and the EdU-positive cell number increased obviously in the miR-586 group but decreased clearly in the anti-miR-586 group. In the miR-586 group, cells at G0/G1 stage and apoptosis cells significantly decreased, while cells at G2/M and S stages and invasive and metastatic cells significantly increased compared to the control and blank groups; however, opposite trends were found in the anti-miR-586 group. Downregulation of miR-586 expression in OS may inhibit cell proliferation, invasion and metastasis, and promote cell apoptosis.

Mascarenhas L, Felgenhauer JL, Bond MC, et al.
Pilot Study of Adding Vincristine, Topotecan, and Cyclophosphamide to Interval-Compressed Chemotherapy in Newly Diagnosed Patients With Localized Ewing Sarcoma: A Report From the Children's Oncology Group.
Pediatr Blood Cancer. 2016; 63(3):493-8 [PubMed] Article available free on PMC after 01/03/2017 Related Publications
BACKGROUND: The combination of topotecan and cyclophosphamide is active in relapsed Ewing sarcoma family of tumors (ESFT). The feasibility of adding these agents combined with vincristine (vincristine-topotecan-cyclophosphamide [VTc]) to standard five-drug chemotherapy with vincristine-doxorubicin-cyclophosphamide (VDC) and ifosfamide-etoposide (IE) administered in an interval-compressed (2-week instead of 3-week intervals) schedule was investigated.
PROCEDURE: Newly diagnosed patients with localized ESFT < 31 years, with good performance status and adequate organ function were eligible. Seventeen alternating cycles of chemotherapy with VTc, VDC, and IE were administered at 2-week intervals. Local control (LC) of the primary tumor occurred following six cycles. Primary endpoints were the ability to deliver chemotherapy in an interval-compressed schedule, and the rate of grade 3 or greater nonhematologic toxicity and grade 4 hematologic toxicity, which delayed chemotherapy by ≥2 weeks. Secondary endpoints were event-free survival (EFS) and overall survival (OS).
RESULTS: Thirty-five patients with a median age of 11 years were enrolled. The mean time to last dose of chemotherapy prior to LC was 12.6 ± 1.4 weeks and 45.5% of patients received intended chemotherapy without any delay prior to LC. There were no toxic deaths or unexpected toxicities. Five-year EFS was 79.6% (95% confidence interval [CI]: 61.8-89.7%) and 5-year OS was 88% (95% CI: 71.4-95.3%).
CONCLUSIONS: The addition of VTc to standard therapy was tolerable with sufficient interval compression compared to historical standard 3-week cycles.

Martins-Neves SR, Paiva-Oliveira DI, Wijers-Koster PM, et al.
Chemotherapy induces stemness in osteosarcoma cells through activation of Wnt/β-catenin signaling.
Cancer Lett. 2016; 370(2):286-95 [PubMed] Related Publications
Development of resistance represents a major drawback in osteosarcoma treatment, despite improvements in overall survival. Treatment failure and tumor progression have been attributed to pre-existing drug-resistant clones commonly assigned to a cancer stem-like phenotype. Evidence suggests that non stem-like cells, when submitted to certain microenvironmental stimuli, can acquire a stemness phenotype thereby strengthening their capacity to handle with stressful conditions. Here, using osteosarcoma cell lines and a mouse xenograft model, we show that exposure to conventional chemotherapeutics induces a phenotypic cell transition toward a stem-like phenotype. This associates with activation of Wnt/β-catenin signaling, up-regulation of pluripotency factors and detoxification systems (ABC transporters and Aldefluor activity) that ultimately leads to chemotherapy failure. Wnt/β-catenin inhibition combined with doxorubicin, in the MNNG-HOS cells, prevented the up-regulation of factors linked to transition into a stem-like state and can be envisaged as a way to overcome adaptive resistance. Finally, the analysis of the public R2 database, containing microarray data information from diverse osteosarcoma tissues, revealed a correlation between expression of stemness markers and a worse response to chemotherapy, which provides evidence for drug-induced phenotypic stem cell state transitions in osteosarcoma.

Yang J, Zhu B, Fu K, Yang Q
The long-term outcomes following the use of inactivated autograft in the treatment of primary malignant musculoskeletal tumor.
J Orthop Surg Res. 2015; 10:177 [PubMed] Article available free on PMC after 01/03/2017 Related Publications
BACKGROUND: Biological reconstruction surgery is a tough but alluring option for treating primary malignant musculoskeletal tumors. In this article, we evaluate the clinical outcomes of primary malignant musculoskeletal tumors treated with inactivated autograft using alcohol.
METHOD: In this article, we include 58 patients who had primary malignant bone tumors treated with wide resection and recycling autograft reconstruction using alcohol between January 2003 and January 2013. The outcomes were measured by recurrence, functional status, and complications. Functional status was assessed according to the Musculoskeletal Tumor Society Score (MSTSS). The Kaplan-Meier survival curve was used to evaluate the survival rate of the patient.
RESULT: The most common tumor was osteosarcoma (31 cases) followed by chondrosarcoma (10 cases). The tibia was the most frequently involved skeletal site (27 cases) followed by femur (26 cases). The median follow-up period was 54 months, ranging from 18 to 96 months. In 58 patients, 12 were with local recurrence (20.7 %), 16 with lung metastasis (27.6 %), and 13 with complications (22.4 %). The main complication was infection (8 cases). The autografts survived in 49 patients (84.5 %). The mean MSTSS score was 78.5 %, ranging from 47 to 98 %.
CONCLUSION: Recycling autograft reconstruction using alcohol had favorable clinical outcomes to some degree; however, the recurrence and complication rates seem to be high. Thus, we should apply this method with caution and choose the patients with strict surgical indication.

Bibbo C, Newman AS, Lackman RD, et al.
A simplified approach to reconstruction of hemipelvectomy defects with lower extremity free fillet flaps to minimize ischemia time.
J Plast Reconstr Aesthet Surg. 2015; 68(12):1750-4 [PubMed] Related Publications
External hemipelvectomy associated with trauma or during the operative management of musculoskeletal sarcomas may yield a soft tissue defect that can only be sufficiently covered by free tissue transfers. The application of "spare-parts surgery," such as a fillet of leg or thigh flap, uses distal uninvolved parts that are otherwise viable tissues as donor tissues to cover defects. This concept has great utility to achieve soft tissue coverage in challenging cases, such as hemipelvectomy. However, during such complicated and time-consuming cases, prolonged ischemia time of the proposed donor tissues can be problematic. We describe a technique developed by the senior author (SJK) that minimizes the ischemia time of donor free tissues during external hemipelvectomy. This technique is applicable to other surgeries where filleted spare parts are the donor-site source for free tissue transfer.

Yan GN, Lv YF, Guo QN
Advances in osteosarcoma stem cell research and opportunities for novel therapeutic targets.
Cancer Lett. 2016; 370(2):268-74 [PubMed] Related Publications
Osteosarcoma is the most common type of bone cancer, especially in children and young adults. The primary treatment for osteosarcoma is a combination of surgery and chemotherapy, however prognoses remain poor due to chemoresistance and early metastases. Osteosarcoma stem cells appear to play central roles in tumor recurrence, metastases and chemoresistance via self-renewal and differentiation. Targeting these cells may provide a novel strategy in the treatment of osteosarcoma. This review summarizes current knowledge of this rare phenotype and recent advances in understanding the functions OSCs (osteosarcoma stem cells) in osteosarcoma, with the aim of improving therapies in the future.

Aghighi M, Golovko D, Ansari C, et al.
Imaging Tumor Necrosis with Ferumoxytol.
PLoS One. 2015; 10(11):e0142665 [PubMed] Article available free on PMC after 01/03/2017 Related Publications
OBJECTIVE: Ultra-small superparamagnetic iron oxide nanoparticles (USPIO) are promising contrast agents for magnetic resonance imaging (MRI). USPIO mediated proton relaxation rate enhancement is strongly dependent on compartmentalization of the agent and can vary depending on their intracellular or extracellular location in the tumor microenvironment. We compared the T1- and T2-enhancement pattern of intracellular and extracellular USPIO in mouse models of cancer and pilot data from patients. A better understanding of these MR signal effects will enable non-invasive characterizations of the composition of the tumor microenvironment.
MATERIALS AND METHODS: Six 4T1 and six MMTV-PyMT mammary tumors were grown in mice and imaged with ferumoxytol-enhanced MRI. R1 relaxation rates were calculated for different tumor types and different tumor areas and compared with histology. The transendothelial leakage rate of ferumoxytol was obtained by our measured relaxivity of ferumoxytol and compared between different tumor types, using a t-test. Additionally, 3 patients with malignant sarcomas were imaged with ferumoxytol-enhanced MRI. T1- and T2-enhancement patterns were compared with histopathology in a descriptive manner as a proof of concept for clinical translation of our observations.
RESULTS: 4T1 tumors showed central areas of high signal on T1 and low signal on T2 weighted MR images, which corresponded to extracellular nanoparticles in a necrotic core on histopathology. MMTV-PyMT tumors showed little change on T1 but decreased signal on T2 weighted images, which correlated to compartmentalized nanoparticles in tumor associated macrophages. Only 4T1 tumors demonstrated significantly increased R1 relaxation rates of the tumor core compared to the tumor periphery (p<0.001). Transendothelial USPIO leakage was significantly higher for 4T1 tumors (3.4±0.9x10-3 mL/min/100cm3) compared to MMTV-PyMT tumors (1.0±0.9x10-3 mL/min/100 cm3). Likewise, ferumoxytol imaging in patients showed similar findings with high T1 signal in areas of tumor necrosis and low signal in areas of intracellularly compartmentalized iron.
CONCLUSION: Differential T1- and T2-enhancement patterns of USPIO in tumors enable conclusions about their intracellular and extracellular location. This information can be used to characterize the composition of the tumor microenvironment.

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