Bone Cancers
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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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Information for Patients and the Public
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Ewing's Sarcoma
Primary Lymphoma of Bone
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Information Patients and the Public (9 links)

Information for Health Professionals / Researchers (11 links)

Latest Research Publications

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

Jahangiri FR, Al Eissa S, Jahangiri AF, Al-Habib A
Intraoperative neurophysiological monitoring during sacrectomy procedures.
Neurodiagn J. 2013; 53(4):312-22 [PubMed] Related Publications
Previously intraoperative neurophysiological monitoring (IONM) has not been used along with a computer based navigation system for en bloc resection of a sacral Ewing sarcoma. In order to improve the post-operative neurological outcome of the patient we decided to include IONM in our procedure. A partial or complete resection of a sacral tumor may result in the loss of neurological functions due to close proximity of vascular, neural, and visceral structures. A prolonged two-stage surgical procedure may be a high risk procedure for position related brachial plexus injury. An 18-year-old male presented with left lower extremity weakness, which worsened with gait. His MRI was consistent with a sacral mass causing compression on the left S1 and S2 roots. A surgical resection was planned with anterior and posterior approaches. IONM helped guide the surgical team to prevent damaging the sacral roots on the normal side (right) and position related upper extremity brachial plexus injuries. Our technique involving IONM can be used safely for accurate en bloc removal of a sacral tumor with a safe margin while protecting the neural function and minimizing recurrence. This case report demonstrates that intraoperative neurophysiological monitoring was useful in identifying and reversing impending nerve injury during sacrectomy surgery. Significant changes were seen in ulnar and posterior tibial somatosensory evoked potentials (SSEPs). We recommend that IONM should be considered for safe margin en bloc sacral tumor resection and prevention of injury to the sacral root and brachial plexus.

Related: Ewing's Sarcoma

Farahat A, Magdy N, Elaffandi A
Primary myxoid chondrosarcoma of the breast.
Ann R Coll Surg Engl. 2014; 96(1):112E-411E [PubMed] Related Publications
Primary breast chondrosarcoma has been rarely reported in the literature. Conservative breast surgery has never been part of the management of previously reported cases. Surgery remains the mainstay management of such a disease as it is resistant to chemotherapy and radiotherapy. In this report, we present a case of rare primary myxoid chondrosarcoma of the breast that was managed successfully with a conservative approach.

Related: Breast Cancer Chondrosarcoma

Johal S, Ralston S, Knight C
Mifamurtide for high-grade, resectable, nonmetastatic osteosarcoma following surgical resection: a cost-effectiveness analysis.
Value Health. 2013; 16(8):1123-32 [PubMed] Related Publications
OBJECTIVES: Mifamurtide is an immune macrophage stimulant that when added to standard chemotherapy has demonstrated survival benefit for newly diagnosed osteosarcoma. The objectives of this study were to investigate the cost-effectiveness of adding mifamurtide to standard three- or four-agent chemotherapy for high-grade, resectable, nonmetastatic osteosarcoma following surgical resection and the issues of obtaining robust cost-effectiveness estimates for ultra-orphan drugs, given the shortage of data.
METHODS: An economic evaluation was conducted from the perspective of the UK's National Health Service as part of the manufacturer's submission to the National Institute for Health and Care Excellence. The disease process was simplified to a transition through a series of health states, modeled by using a Markov approach. Data to inform the model were derived from patient-level data of Study INT-0133, published literature, and expert opinion. The final efficacy measure was life-years gained (LYG), and utilities were used to obtain quality-adjusted life-years (QALYs).
RESULTS: For a 60-year time frame and a discount rate of 3.5% for outcomes, patients receiving mifamurtide benefited from an average additional 1.57 years of life and 1.34 QALYs, compared with patients receiving chemotherapy alone, giving an incremental cost-effectiveness ratio (ICER) of £58,737 per LYG and £68,734 per QALY. Because treatment effects were both substantial in restoring health and sustained over a very long period, the National Institute for Health and Care Excellence changed its guidance to allow a discount of 1.5% for outcomes to be applied in these special circumstances. By using this discount factor, it was found that patients receiving mifamurtide had an average additional 2.58 years of life and 2.20 QALYs compared with patients receiving chemotherapy alone, resulting in an ICER of £35,765 per LYG and £41,933 per QALY.
CONCLUSION: Mifamurtide's ICER is cost-effective compared with that of other orphan and ultra-orphan drugs, for which prices and corresponding cost-effectiveness estimates are high.

Related: Osteosarcoma

Mücke T, Mitchell DA, Tannapfel A, et al.
Effect of neoadjuvant treatment in the management of osteosarcomas of the head and neck.
J Cancer Res Clin Oncol. 2014; 140(1):127-31 [PubMed] Related Publications
PURPOSE: Osteosarcomas of the craniomaxillofacial region in adults are rare malignant tumors with many sites of origin. The purpose of this study was to analyze the outcome of adult patients suffering from osteosarcomas and investigate whether neoadjuvant chemotherapy would be beneficial to overall outcome.
PATIENTS AND METHODS: The medical records of 36 patients treated during 2002-2012 were reviewed. All patients suffered from primary osteosarcomas of the craniomaxillofacial region.
RESULTS: The mean survival of patients was 64.49 ± 23.52 months. The 2- and 5-year overall survival rates in the neoadjuvant treatment group were 100 and 66.7 %; in the surgery only group, the overall survival rates were 66.7 and 41.7 %, respectively. The neoadjuvant treatment (p = 0.017), tumor size (p = 0.004), tumor location (p = 0.02), and age (p < 0.0001) were significant parameters influencing survival, whereas other tumor-related or demographic factors had no significant influence on survival.
CONCLUSIONS: Early identification of osteosarcoma of the craniomaxillofacial region and combined treatment by neoadjuvant chemotherapy with radical surgery are the most important strategies in dealing with these sarcomas. If possible, this treatment option should be followed unless contraindicated by other factors.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology Osteosarcoma

Incesu Z, Hatipoğlu I, Sivas H, et al.
Effects of fibronectin and type IV collagen on osteosarcoma cell apoptosis.
Indian J Exp Biol. 2013; 51(10):789-96 [PubMed] Related Publications
The aims of this study are the investigation of the effects of fibronectin and type IV collagen extracellular matrix proteins and the role of caspase-3 and -9 on cis-platin induced U2-OS apoptosis were studied. First the cytotoxic effects of cis-platin on cell system were investigated by colorimetric method and than morphological and ELISA analysis were used for determination of cell apoptosis when induced with cis-platin. In addition, after adhering the cells to fibronection or type IV collagen proteins, the apoptotic rate and the effects of caspase-3 and -9 were also investigated by ELISA in presence of specific inhibitors. U2-OS cells showed 20% cytotoxicity after treatment with 2.4 microM of cis-platin for 48 h. Morphological and the numerical data showed that cis-platin was able to induced apoptosis on cells as a dose-dependent manner. Caspase-3 and -9 inhibitors inhibited cis-platin-induced apoptosis in U2-OS cells, respectively. The binding of cells to 10 microg/mL of fibronectin but not type IV collagen enhanced the apoptosis about 2.5 fold that effects inhibited with caspase-3 inhibitor. The caspase-3 and -9 are involved in the apoptotic signals induced by cis-platin in U2-OS. The binding to fibronectin, but not type IV collagen enhanced the apoptotic response of U2-OS and fibronectin-dependent apoptosis was activated by caspase-3. These finding might be useful for patients to fight against osteosarcoma.

Related: Apoptosis Cisplatin Osteosarcoma

Raphael B, Hwang S, Lefkowitz RA, et al.
Biopsy of suspicious bone lesions in patients with a single known malignancy: prevalence of a second malignancy.
AJR Am J Roentgenol. 2013; 201(6):1309-14 [PubMed] Related Publications
OBJECTIVE: The probability that a suspicious bone lesion in a patient with one known malignancy is actually due to a second, previously unknown primary malignancy has been reported to be 2-8%. We sought to determine this prevalence as well as that of benign diagnoses in a larger number of patients in a tertiary cancer center.
MATERIALS AND METHODS: The medical records of 482 consecutive patients (254 women and 228 men) with only one known primary malignancy each (excluding nonmelanoma skin cancer) and who underwent biopsy of a suspicious bone lesion were retrospectively reviewed. The results of bone biopsy were classified as benign, metastasis of the known primary malignancy, due to a second primary malignancy, or nondiagnostic or indeterminate.
RESULTS: In 103 of 482 (21%) patients, bone biopsy results were benign, 316 (66%) were due to metastases of the known malignancy, 15 (3%) were due to a second malignancy, and 48 (10%) were nondiagnostic or indeterminate. Second malignancies included osteosarcoma (n = 4); soft-tissue sarcoma (n = 2); lymphoma (n = 2); plasma cell malignancy (n = 2); and lung cancer, thyroid cancer, renal cancer, chondrosarcoma, and carcinoma of unknown primary (n = 1 each).
CONCLUSION: In 3% of patients with one known malignancy and a suspicious bone lesion, the lesion was due to a previously unknown second malignancy; in 21% of patients, the lesion was benign. Bone biopsy is recommended in the management of patients with one known cancer and a suspicious bone lesion only if the presence of a second malignancy would alter clinical management.

Puri A, Pruthi M, Gulia A
Outcomes after limb sparing resection in primary malignant pelvic tumors.
Eur J Surg Oncol. 2014; 40(1):27-33 [PubMed] Related Publications
AIM: To evaluate morbidity, oncologic results and functional outcome in patients with malignant tumors of pelvis treated with limb sparing resection.
METHODS: Between March 2002 and November 2010, 106 cases of non metastatic malignant pelvic tumors were treated with limb sparing resections of pelvis. Diagnosis included chondrosarcoma (65), Ewing's sarcoma (25), osteogenic sarcoma (10), synovial sarcoma (3) and malignant fibrous histiocytoma, high grade sarcoma, epitheloid hemangiothelioma (1 each). Three patients had intralesional surgery because of erroneous pre-operative diagnosis of benign tumor and were excluded from final analysis. Remaining 103 patients underwent limb sparing resections with intent to achieve tumor free margins. In 1 case, an intraoperative cardiac event lead to the surgery being abandoned. Reconstruction was done in 2 of 38 cases that did not include resection of acetabulum. For 64 resections involving acetabulum various reconstruction modalities were used.
RESULTS: Surgical margins were involved in 20 patients. Forty five patients had complications. 91 patients were available for follow up. Follow up of survivors ranged from 24 to 122 months (mean 55 months).Twenty one patients (23%) had local recurrence. Sixty patients are currently alive, 46 being continuously disease free. Overall survival was 67% at 5 years. Patients in whom acetabulum was retained had better function (mean MSTS score 27) compared to patients in whom acetabulum was resected (mean MSTS score 22).
CONCLUSIONS: Though complex and challenging, limb sparing surgery in non metastatic malignant tumors is oncologically safe and has better functional outcomes than after an amputation surgery.

Related: Osteosarcoma Soft Tissue Sarcomas Childhood Soft Tissue Sarcomas Soft Tissue Sarcoma Ewing's Sarcoma Synovial Sarcoma

Kansara M, Leong HS, Lin DM, et al.
Immune response to RB1-regulated senescence limits radiation-induced osteosarcoma formation.
J Clin Invest. 2013; 123(12):5351-60 [PubMed] Free Access to Full Article Related Publications
Ionizing radiation (IR) and germline mutations in the retinoblastoma tumor suppressor gene (RB1) are the strongest risk factors for developing osteosarcoma. Recapitulating the human predisposition, we found that Rb1+/- mice exhibited accelerated development of IR-induced osteosarcoma, with a latency of 39 weeks. Initial exposure of osteoblasts to carcinogenic doses of IR in vitro and in vivo induced RB1-dependent senescence and the expression of a panel of proteins known as senescence-associated secretory phenotype (SASP), dominated by IL-6. RB1 expression closely correlated with that of the SASP cassette in human osteosarcomas, and low expression of both RB1 and the SASP genes was associated with poor prognosis. In vivo, IL-6 was required for IR-induced senescence, which elicited NKT cell infiltration and a host inflammatory response. Mice lacking IL-6 or NKT cells had accelerated development of IR-induced osteosarcomas. These data elucidate an important link between senescence, which is a cell-autonomous tumor suppressor response, and the activation of host-dependent cancer immunosurveillance. Our findings indicate that overcoming the immune response to senescence is a rate-limiting step in the formation of IR-induced osteosarcoma.

Related: Cytokines Osteosarcoma

Tsagaraki I, Phenekos C, Tsilibary E, Tzinia A
Calcitonin-induced NF-κB activation up-regulates fibronectin expression in MG63 osteosarcoma cells.
Anticancer Res. 2013; 33(11):4901-6 [PubMed] Related Publications
Salmon calcitonin has been used extensively as a therapeutic tool in the regulation of bone remodeling. However, there is a growing body of evidence indicating that the calcitonin peptides are involved in regulation of cell growth, differentiation, survival and tissue development. In the present study, we investigated the effect of calcitonin in cell matrix interactions in MG63 cell line. Our results demonstrated that calcitonin increases cell growth of MG63 osteosarcoma cells in parallel with serine/threonine protein kinase B (AKT/PKB) activation. Moreover, calcitonin induced up-regulation of fibronectin expression in a nuclear factor-kappa B (NF-κB)-dependent manner, accompanied by enhanced enzymatic activity of matrix metalloproteinase-9 (MMP-9) and increased expression of tissue inhibitors of MMP-1 and -2. MMP-9 stimulation with calcitonin was accompanied by an increase in protein expression of the α5β1 integrin receptor. To our knowledge, our results demonstrate, for the first time, that calcitonin is a potent inducer of fibronectin, an extacellular matrix component that is suggested to have a pro-oncogenic and healing effect, in a NF-κB-dependent manner.

Related: MMP9: matrix metallopeptidase 9 Osteosarcoma AKT1 Signal Transduction

Lim JB, Sharma H, MacDuff E, Reece AT
Primary osteosarcoma of the spine: a review of 10 cases.
Acta Orthop Belg. 2013; 79(4):457-62 [PubMed] Related Publications
The authors describe 10 cases of osteosarcoma of the spine treated between January 1951 and December 2010, and obtained from the Tumour Registry of their hospital. The mean age at presentation was 38.8 years (range: 16-73 years); the mean duration of symptoms was 5.1 months (range: 3 weeks-1 year). Pain was the commonest complaint (9 patients), followed by neurological compromise (6 patients). The thoracic spine and male gender were predominant. Seven patients underwent marginal resection, 3 underwent intralesional resection. All, except one, had adjuvant chemotherapy and radiotherapy, pre- and/or postoperatively. This rare sarcoma has a dismal prognosis : the median survival period was only 23 years. The 1-year, 3-year and 5-year survival rates were 80%, 40% and 20%. Astonishingly, marginal resection (7 cases) did not lead to a longer survival than intralesional resection (3 cases): respectively 30 months and 42 months. Quite logically, local recurrence in 6 patients was linked to a survival of only 36 months, while the other 4 patients survived 52 months. Age below 40 was a positive factor, but not significantly. All patients had a reasonable quality of life with outcomes consistent with the available literature. Recent literature stresses that there is a trend toward improved survival with en bloc resection.

Related: Osteosarcoma

Huang WY, Tan WL, Geng DY, et al.
Imaging findings of the spinal peripheral Ewing's sarcoma family of tumours.
Clin Radiol. 2014; 69(2):179-85 [PubMed] Related Publications
AIM: To present the neuroradiological and clinical characteristics of Ewing's sarcoma family of tumours (ESFTs) and to increase awareness of this neoplasm.
MATERIALS AND METHODS: The magnetic resonance imaging (MRI) features and clinical presentations of seven patients with pathologically documented ESFTs were retrospectively analysed. The tumour location, morphological features, signal intensity, contrast enhancement characteristics, involvement of the paraspinal soft tissues, and adjacent bony structures were assessed.
RESULTS: Most of the ESFTs in young adults were well-circumscribed. The present study demonstrated that ESFTs often have a hypo- or iso-intense signal on T1-weighted imaging and an iso-intense signal on T2-weighted imaging. Spinal ESFTs tended to present homogeneous signal intensity and diffuse enhancement. ESFTs are more likely to occur in the thoracic spine and later to infiltrate into the paraspinal area or vertebral bone. A broad dural attachment is another common feature in the cases presented here.
CONCLUSIONS: ESFT is a rare neoplasm that can have significant overlap in imaging appearance compared with other spinal neoplasms. A well-demarcated extradural mass invading the paraspinal soft or vertebral bones, with iso-intense on T2 weighted imaging and homogeneous enhancement could facilitate the diagnosis of spinal ESFT.

Related: Ewing's Sarcoma

Frassanito P, Massimi L, Rigante M, et al.
Recurrent and self-remitting sixth cranial nerve palsy: pathophysiological insight from skull base chondrosarcoma.
J Neurosurg Pediatr. 2013; 12(6):633-6 [PubMed] Related Publications
Palsy of the abducens nerve is a neurological sign that has a wide range of causes due to the nerve's extreme vulnerability. Need of immediate neuroimaging is a matter of debate in the literature, despite the risks of delaying the diagnosis of a skull base tumor. The authors present 2 cases of skull base tumors in which the patients presented with recurrent and self-remitting episodes of sixth cranial nerve palsy (SCNP). In both cases the clinical history exceeded 1 year. In a 17-year-old boy the diagnosis was made because of the onset of headache when the tumor reached a very large size. In a 12-year-old boy the tumor was incidentally diagnosed when it was still small. In both patients surgery was performed and the postoperative course was uneventful. Pathological diagnosis of the tumor was consistent with that of a chondrosarcoma in both cases. Recurrent self-remitting episodes of SCNP, resembling transitory ischemic attacks, may be the presenting sign of a skull base tumor due to the anatomical relationships of these lesions with the petroclival segment of the sixth cranial nerve. Physicians should promptly recommend neuroimaging studies if SCNP presents with this peculiar course.

Related: Chondrosarcoma

Aryee DN, Niedan S, Ban J, et al.
Variability in functional p53 reactivation by PRIMA-1(Met)/APR-246 in Ewing sarcoma.
Br J Cancer. 2013; 109(10):2696-704 [PubMed] Article available free on PMC after 12/11/2014 Related Publications
BACKGROUND: Though p53 mutations are rare in ES, there is a strong indication that p53 mutant tumours form a particularly bad prognostic group. As such, novel treatment strategies are warranted that would specifically target and eradicate tumour cells containing mutant p53 in this subset of ES patients.
METHODS: PRIMA-1(Met), also known as APR-246, is a small organic molecule that has been shown to restore tumour-suppressor function primarily to mutant p53 and also to induce cell death in various cancer types. In this study, we interrogated the ability of APR-246 to induce apoptosis and inhibit tumour growth in ES cells with different p53 mutations.
RESULTS: APR-246 variably induced apoptosis, associated with Noxa, Puma or p21(WAF1) upregulation, in both mutant and wild-type p53 harbouring cells. The apoptosis-inducing capability of APR-246 was markedly reduced in ES cell lines transfected with p53 siRNA. Three ES cell lines established from the same patient at different stages of the disease and two cell lines of different patients with identical p53 mutations all exhibited different sensitivities to APR-246, indicating cellular context dependency. Comparative transcriptome analysis on the three cell lines established from the same patient identified differential expression levels of several TP53 and apoptosis-associated genes such as APOL6, PENK, PCDH7 and MST4 in the APR-246-sensitive cell line relative to the less APR-246-sensitive cell lines.
CONCLUSION: This is the first study reporting the biological response of Ewing sarcoma cells to APR-246 exposure and shows gross variability in responses. Our study also proposes candidate genes whose expression might be associated with ES cells' sensitivity to APR-246. With APR-246 currently in early-phase clinical trials, our findings call for caution in considering it as a potential adjuvant to conventional ES-specific chemotherapeutics.

Related: Apoptosis Ewing's Sarcoma TP53

Tavanti E, Sero V, Vella S, et al.
Preclinical validation of Aurora kinases-targeting drugs in osteosarcoma.
Br J Cancer. 2013; 109(10):2607-18 [PubMed] Article available free on PMC after 12/11/2014 Related Publications
BACKGROUND: Aurora kinases are key regulators of cell cycle and represent new promising therapeutic targets in several human tumours.
METHODS: Biological relevance of Aurora kinase-A and -B was assessed on osteosarcoma clinical samples and by silencing these genes with specific siRNA in three human osteosarcoma cell lines. In vitro efficacy of two Aurora kinases-targeting drugs (VX-680 and ZM447439) was evaluated on a panel of four drug-sensitive and six drug-resistant human osteosarcoma cell lines.
RESULTS: Human osteosarcoma cell lines proved to be highly sensitive to both drugs. A decreased drug sensitivity was observed in doxorubicin-resistant cell lines, most probably related to ABCB1/MDR1 overexpression. Both drugs variably induced hyperploidy and apoptosis in the majority of cell lines. VX-680 also reduced in vitro cell motility and soft-agar cloning efficiency. Drug association experiments showed that VX-680 positively interacts with all conventional drugs used in osteosarcoma chemotherapy, overcoming the cross-resistance observed in the single-drug treatments.
CONCLUSION: Aurora kinase-A and -B represent new candidate therapeutic targets for osteosarcoma. In vitro analysis of the Aurora kinases inhibitors VX-680 and ZM447439 indicated in VX-680 a new promising drug of potential clinical usefulness in association with conventional osteosarcoma chemotherapeutic agents.

Related: Osteosarcoma

Mujtaba SS, Haroon S, Faridi N
Primary chondrosarcoma of breast.
J Coll Physicians Surg Pak. 2013; 23(10):754-5 [PubMed] Related Publications
Mammary sarcomas are heterogeneous group of malignant neoplasms that arise from the mammary stroma. They are uncommon tumours and most of these occur as a component of other tumours. Of the malignant breast mesenchymal tumours, pure sarcomas which lack epithelial component are rarer as these comprise only 0.5% of the breast tumours. Of these, the most common are angiosarcomas, liposarcomas and osteosarcomas. Pure, primary and De novo chondrosarcomas features as one of the rarer types of sarcomas of breast and should be differentiated from Phylloides tumours with chondromatous areas by extensive sampling which also excludes ductal elements in the tumour. This case report describes very rare primary breast sarcoma i.e. chondrosarcoma in a female aged 40 years which was treated by simple mastectomy.

Related: Breast Cancer Chondrosarcoma

Van Rossem C, Pauwels P, Somville J, et al.
Sarcomatous degeneration in fibrous dysplasia of the rib cage.
Ann Thorac Surg. 2013; 96(4):e89-90 [PubMed] Related Publications
Malignant degeneration in fibrous dysplasia is a rare occurrence. Most cases are reported in polyostotic fibrous dysplasia with predisposition of the femur, tibia, maxilla, and mandible. The most commonly observed malignant tumors are osteosarcoma, fibrosarcoma, and chondrosarcoma. We describe a case of a low-grade osteosarcoma occurring in polyostotic fibrous dysplasia of the rib cage in a 50-year-old man.

Related: Osteosarcoma

Jeys L, Matharu GS, Nandra RS, Grimer RJ
Can computer navigation-assisted surgery reduce the risk of an intralesional margin and reduce the rate of local recurrence in patients with a tumour of the pelvis or sacrum?
Bone Joint J. 2013; 95-B(10):1417-24 [PubMed] Related Publications
We hypothesised that the use of computer navigation-assisted surgery for pelvic and sacral tumours would reduce the risk of an intralesional margin. We reviewed 31 patients (18 men and 13 women) with a mean age of 52.9 years (13.5 to 77.2) in whom computer navigation-assisted surgery had been carried out for a bone tumour of the pelvis or sacrum. There were 23 primary malignant bone tumours, four metastatic tumours and four locally advanced primary tumours of the rectum. The registration error when using computer navigation was < 1 mm in each case. There were no complications related to the navigation, which allowed the preservation of sacral nerve roots (n = 13), resection of otherwise inoperable disease (n = 4) and the avoidance of hindquarter amputation (n = 3). The intralesional resection rate for primary tumours of the pelvis and sacrum was 8.7% (n = 2): clear bone resection margins were achieved in all cases. At a mean follow-up of 13.1 months (3 to 34) three patients (13%) had developed a local recurrence. The mean time alive from diagnosis was 16.8 months (4 to 48). Computer navigation-assisted surgery is safe and has reduced our intralesional resection rate for primary tumours of the pelvis and sacrum. We recommend this technique as being worthy of further consideration for this group of patients.

Related: Chondrosarcoma

Lu C, Venneti S, Akalin A, et al.
Induction of sarcomas by mutant IDH2.
Genes Dev. 2013; 27(18):1986-98 [PubMed] Article available free on PMC after 15/03/2014 Related Publications
More than 50% of patients with chondrosarcomas exhibit gain-of-function mutations in either isocitrate dehydrogenase 1 (IDH1) or IDH2. In this study, we performed genome-wide CpG methylation sequencing of chondrosarcoma biopsies and found that IDH mutations were associated with DNA hypermethylation at CpG islands but not other genomic regions. Regions of CpG island hypermethylation were enriched for genes implicated in stem cell maintenance/differentiation and lineage specification. In murine 10T1/2 mesenchymal progenitor cells, expression of mutant IDH2 led to DNA hypermethylation and an impairment in differentiation that could be reversed by treatment with DNA-hypomethylating agents. Introduction of mutant IDH2 also induced loss of contact inhibition and generated undifferentiated sarcomas in vivo. The oncogenic potential of mutant IDH2 correlated with the ability to produce 2-hydroxyglutarate. Together, these data demonstrate that neomorphic IDH2 mutations can be oncogenic in mesenchymal cells.

Related: Chondrosarcoma

Jaing TH, Yang CP, Hung IJ, et al.
Phyllodes tumor in survivors of childhood osteosarcoma: a single institution's experience.
J Pediatr Hematol Oncol. 2014; 36(1):e36-8 [PubMed] Related Publications
We evaluate the incidence of second neoplasms in 86 patients with osteosarcoma (OS) of the extremities treated with different protocols of adjuvant chemotherapy. Three patients developed phyllodes tumors as the second neoplasm. One of these patients simultaneously developed a third cancer with therapy-related acute myeloid leukemia. The sites of primary OS were the tibia (2) and humerus (1). None had received prior radiotherapy before excision of phyllodes tumor. All the patients were female with a median age of 21.7 years at the time of presentation. As yet, that precise causation is unclear, but it can increase our understanding of carcinogenic processes, in general.

Related: Acute Myeloid Leukemia (AML) Childhood Acute Myeloid Leukaemia AML - Molecular Biology Osteosarcoma

Lauvrak SU, Munthe E, Kresse SH, et al.
Functional characterisation of osteosarcoma cell lines and identification of mRNAs and miRNAs associated with aggressive cancer phenotypes.
Br J Cancer. 2013; 109(8):2228-36 [PubMed] Article available free on PMC after 15/10/2014 Related Publications
BACKGROUND: Osteosarcoma is the most common primary malignant bone tumour, predominantly affecting children and adolescents. Cancer cell line models are required to understand the underlying mechanisms of tumour progression and for preclinical investigations.
METHODS: To identify cell lines that are well suited for studies of critical cancer-related phenotypes, such as tumour initiation, growth and metastasis, we have evaluated 22 osteosarcoma cell lines for in vivo tumorigenicity, in vitro colony-forming ability, invasive/migratory potential and proliferation capacity. Importantly, we have also identified mRNA and microRNA (miRNA) gene expression patterns associated with these phenotypes by expression profiling.
RESULTS: The cell lines exhibited a wide range of cancer-related phenotypes, from rather indolent to very aggressive. Several mRNAs were differentially expressed in highly aggressive osteosarcoma cell lines compared with non-aggressive cell lines, including RUNX2, several S100 genes, collagen genes and genes encoding proteins involved in growth factor binding, cell adhesion and extracellular matrix remodelling. Most notably, four genes-COL1A2, KYNU, ACTG2 and NPPB-were differentially expressed in high and non-aggressive cell lines for all the cancer-related phenotypes investigated, suggesting that they might have important roles in the process of osteosarcoma tumorigenesis. At the miRNA level, miR-199b-5p and mir-100-3p were downregulated in the highly aggressive cell lines, whereas miR-155-5p, miR-135b-5p and miR-146a-5p were upregulated. miR-135b-5p and miR-146a-5p were further predicted to be linked to the metastatic capacity of the disease.
INTERPRETATION: The detailed characterisation of cell line phenotypes will support the selection of models to use for specific preclinical investigations. The differentially expressed mRNAs and miRNAs identified in this study may represent good candidates for future therapeutic targets. To our knowledge, this is the first time that expression profiles are associated with functional characteristics of osteosarcoma cell lines.

Related: Osteosarcoma

Posthumadeboer J, Piersma SR, Pham TV, et al.
Surface proteomic analysis of osteosarcoma identifies EPHA2 as receptor for targeted drug delivery.
Br J Cancer. 2013; 109(8):2142-54 [PubMed] Article available free on PMC after 15/10/2014 Related Publications
BACKGROUND: Osteosarcoma (OS) is the most common bone tumour in children and adolescents. Despite aggressive therapy regimens, treatment outcomes are unsatisfactory. Targeted delivery of drugs can provide higher effective doses at the site of the tumour, ultimately improving the efficacy of existing therapy. Identification of suitable receptors for drug targeting is an essential step in the design of targeted therapy for OS.
METHODS: We conducted a comparative analysis of the surface proteome of human OS cells and osteoblasts using cell surface biotinylation combined with nano-liquid chromatography - tandem mass spectrometry-based proteomics to identify surface proteins specifically upregulated on OS cells. This approach generated an extensive data set from which we selected a candidate to study for its suitability as receptor for targeted treatment delivery to OS. First, surface expression of the ephrin type-A receptor 2 (EPHA2) receptor was confirmed using FACS analysis. Ephrin type-A receptor 2 expression in human tumour tissue was tested using immunohistochemistry. Receptor targeting and internalisation studies were conducted to assess intracellular uptake of targeted modalities via EPHA2. Finally, tissue micro arrays containing cores of human OS tissue were stained using immunohistochemistry and EPHA2 staining was correlated to clinical outcome measures.
RESULTS: Using mass spectrometry, a total of 2841 proteins were identified of which 156 were surface proteins significantly upregulated on OS cells compared with human primary osteoblasts. Ephrin type-A receptor 2 was highly upregulated and the most abundant surface protein on OS cells. In addition, EPHA2 was expressed in a vast majority of human OS samples. Ephrin type-A receptor 2 effectively mediates internalisation of targeted adenoviral vectors into OS cells. Patients with EPHA2-positive tumours showed a trend toward inferior overall survival.
CONCLUSION: The results presented here suggest that the EPHA2 receptor can be considered an attractive candidate receptor for targeted delivery of therapeutics to OS.

Related: Osteosarcoma

Tian Q, Jia J, Ling S, et al.
A causal role for circulating miR-34b in osteosarcoma.
Eur J Surg Oncol. 2014; 40(1):67-72 [PubMed] Related Publications
PURPOSE: To investigate the associations between plasma miR-34b/c expression levels and osteosarcoma (OS).
SUBJECTS AND METHODS: A case-control study was conducted in 133 patients with OS and 133 controls. MiR-34b/c levels were detected by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assays. Genotyping of SNP rs4938723 was done using the TaqMan assay. The causal association was examined by mendelian randomization analysis.
RESULTS: Plasma miR-34b level was significantly lower in OS patients than in controls (P = 0.001). Expression levels of miR-34b in OS tissues decreased (P = 3.22 × 10(-4)) and was significantly related with its expression in plasma (r = 0.21, P = 0.004). Compared with wild-type TT genotype, the variant genotypes of rs4938723 TC/CC were significantly associated with increased OS risk (TC vs. TT: OR, 1.97 [95% CI: 1.40-2.55], P = 0.021; CC vs. TT: OR, 2.76 [95% CI: 2.00-3.53], P = 0.009; TC + CC vs. TT: OR, 2.16 [95% CI: 1.61-2.70], P = 0.006), consistent with its decreased effect on plasma miR-34b (TC vs. TT: -0.32 (-0.43, -0.21), P < 0.001; CC vs. TT: -0.70 (-0.84, -0.56), P < 0.001; TC + CC vs. TT: -0.42 (-0.53, -0.32), P < 0.001). Adjustment for miR-34b completely abolished the association between SNP rs4938723 and OS risk (P > 0.05). In addition, plasma expression levels of miR-34b were significantly decreased in the metastatic patients compared with that in the non-metastatic ones (P = 0.004).
CONCLUSION: Plasma miR-34b was causally associated with OS risk and related with its metastatic status, suggesting that plasma miR-34b might be a novel biomarker and a potential treatment target for OS.

Hsu CJ, Wu MH, Chen CY, et al.
AMP-activated protein kinase activation mediates CCL3-induced cell migration and matrix metalloproteinase-2 expression in human chondrosarcoma.
Cell Commun Signal. 2013; 11:68 [PubMed] Article available free on PMC after 15/10/2014 Related Publications
Chemokine (C-C motif) ligand 3 (CCL3), also known as macrophage inflammatory protein-1α, is a cytokine involved in inflammation and activation of polymorphonuclear leukocytes. CCL3 has been detected in infiltrating cells and tumor cells. Chondrosarcoma is a highly malignant tumor that causes distant metastasis. However, the effect of CCL3 on human chondrosarcoma metastasis is still unknown. Here, we found that CCL3 increased cellular migration and expression of matrix metalloproteinase (MMP)-2 in human chondrosarcoma cells. Pre-treatment of cells with the MMP-2 inhibitor or transfection with MMP-2 specific siRNA abolished CCL3-induced cell migration. CCL3 has been reported to exert its effects through activation of its specific receptor, CC chemokine receptor 5 (CCR5). The CCR5 and AMP-activated protein kinase (AMPK) inhibitor or siRNA also attenuated CCL3-upregulated cell motility and MMP-2 expression. CCL3-induced expression of MMP-2 and migration were also inhibited by specific inhibitors, and inactive mutants of AMPK, p38 mitogen activated protein kinase (p38 or p38-MAPK), and nuclear factor κB (NF-κB) cascades. On the other hand, CCL3 treatment demonstrably activated AMPK, p38, and NF-κB signaling pathways. Furthermore, the expression levels of CCL3, CCR5, and MMP-2 were correlated in human chondrosarcoma specimens. Taken together, our results indicate that CCL3 enhances the migratory ability of human chondrosarcoma cells by increasing MMP-2 expression via the CCR5, AMPK, p38, and NF-κB pathways.

Related: Chondrosarcoma

Sankar S, Tanner JM, Bell R, et al.
A novel role for keratin 17 in coordinating oncogenic transformation and cellular adhesion in Ewing sarcoma.
Mol Cell Biol. 2013; 33(22):4448-60 [PubMed] Article available free on PMC after 01/05/2014 Related Publications
Oncogenic transformation in Ewing sarcoma is caused by EWS/FLI, an aberrant transcription factor fusion oncogene. Glioma-associated oncogene homolog 1 (GLI1) is a critical target gene activated by EWS/FLI, but the mechanism by which GLI1 contributes to the transformed phenotype of Ewing sarcoma was unknown. In this work, we identify keratin 17 (KRT17) as a direct downstream target gene upregulated by GLI1. We demonstrate that KRT17 regulates cellular adhesion by activating AKT/PKB (protein kinase B) signaling. In addition, KRT17 is necessary for oncogenic transformation in Ewing sarcoma and accounts for much of the GLI1-mediated transformation function but via a mechanism independent of AKT signaling. Taken together, our data reveal previously unknown molecular functions for a cytoplasmic intermediate filament protein, KRT17, in coordinating EWS/FLI- and GLI1-mediated oncogenic transformation and cellular adhesion in Ewing sarcoma.

Related: FLI1 gene AKT1 Ewing's Sarcoma Signal Transduction GLI

Wang Z, Cai H, Lin L, et al.
Upregulated expression of microRNA-214 is linked to tumor progression and adverse prognosis in pediatric osteosarcoma.
Pediatr Blood Cancer. 2014; 61(2):206-10 [PubMed] Related Publications
BACKGROUND: MicroRNA-214 (miR-214) expression has been demonstrated to be dysregulated in human malignancies and to play various roles in tumor progression. While previous study of miRNA expression profiling found that it was one of the most upregulated miRNAs in osteosarcoma signature, the potential role of miR-214 in osteosarcomas has been unclear. Therefore, the aim of this study was to investigate association of miR-214 expression with clinicopathologic features and prognosis in pediatric patients with osteosarcoma.
PROCEDURE: Quantitative real-time reverse transcriptase-polymerase chain reaction analysis was performed to detect expression levels of miR-214 in cancerous and noncancerous bone tissues from 92 children treated for primary osteosarcomas. Then, the clinical significance of miR-214 dysregulation in pediatric osteosarcomas was also determined.
RESULTS: Compared with noncancerous bone tissues, the expression levels of miR-214 were significantly upregulated in osteosarcoma tissues (P < 0.001). High miR-214 expression occurred more frequently in osteosarcoma tissues with large tumor size (P = 0.01), positive metastasis (P = 0.001) and poor response to pre-operative chemotherapy (P = 0.006). Moreover, high miR-214 expression was significantly associated with both shorter overall (P < 0.001) and progression-free survival (PFS; P = 0.001). Multivariate analysis by the Cox proportional hazard model further confirmed that high miR-214 expression was an independent prognostic factor of unfavorable survival in pediatric osteosarcoma (for overall survival: P = 0.008; for PFS: P = 0.01).
CONCLUSION: Our data offer evidence that upregulated expression of miR-214 may be linked to tumor progression and adverse prognosis in pediatric osteosarcoma. Further investigation in prospective studies would appear warranted.

Related: Osteosarcoma

Botchu R, Douis H, Davies AM, et al.
Post-traumatic heterotopic ossification of distal tibiofibular syndesmosis mimicking a surface osteosarcoma.
Clin Radiol. 2013; 68(12):e676-9 [PubMed] Related Publications
AIM: To present the imaging features of post-traumatic heterotopic ossification (HO) of the distal tibiofibular syndesmosis initially suspected to be a surface osteosarcoma.
MATERIALS AND METHODS: A retrospective review was conducted of the presenting complaint and imaging features of patients with a final diagnosis of HO referred over an 8 year period to a specialist orthopaedic oncology centre.
RESULTS: Five patients with HO were identified. All were adult males with an age range of 19-41 years. There was a history of prior ankle trauma in all cases but the significance was not recognized at the time of referral to the specialist centre. There was radiographic evidence of HO arising from the inner aspects of the distal tibia and fibula approximately 3 cm proximal to the ankle joint. The HO was "kissing" in two cases and partially fused (synostosis) in two. The HO in the fifth case was arising on the inner fibular cortex alone. Magnetic resonance imaging (MRI), available in four cases, showed predominantly low signal intensity due to the dense bone formation.
CONCLUSION: The history of prior ankle trauma with ossification arising from the inner aspects of both the distal tibia and fibula is typical of post-traumatic HO and distinguish this benign condition from the rare surface osteosarcoma at this site.

Related: Osteosarcoma

Tome Y, Kimura H, Maehara H, et al.
High lung-metastatic variant of human osteosarcoma cells, selected by passage of lung metastasis in nude mice, is associated with increased expression of α(v)β(3) integrin.
Anticancer Res. 2013; 33(9):3623-7 [PubMed] Related Publications
Altered expression of αvβ3 integrin is associated with tumor progression and metastasis in several types of cancer, including metastatic osteosarcoma. In this study, we demonstrate that in vivo passaging of lung metastasis in nude mice can generate an aggressive variant of human osteosarcoma cells. Experimental metastases were established by injecting 143B human osteosarcoma cells, expressing green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in the cytoplasm, in the tail vein of nude mice. Lung metastases were harvested under fluorescence microscopy from nude mice to establish cell lines which were then injected via the tail vein of additional nude mice. This procedure was repeated for four passages in order to isolate highly metastatic variant sublines. When the parental and metastatic variants were transplanted orthotopically into the tibia of nude mice, the 143B-LM4 variant had the highest metastatic rate, approximately 18-fold higher than the parent (p<0.01). αvβ3 integrin expression was increased approximately 5.6-fold in 143B-LM4 compared to parental cells (p<0.05). Thus, serial passage of lung metastases created a highly metastatic variant of human osteosarcoma cells which had increased expression of αvβ3 integrin, suggesting that αvβ3 integrin plays an essential role in osteosarcoma metastasis. With this highly metastatic variant overexpressing αvβ3 integrin, it will now be possible to further investigate the mechanism by which αvβ3 integrin facilitates metastasis.

Related: Osteosarcoma

Fu HL, Shao L, Wang Q, et al.
A systematic review of p53 as a biomarker of survival in patients with osteosarcoma.
Tumour Biol. 2013; 34(6):3817-21 [PubMed] Related Publications
Osteosarcoma is the most common malignant bone tumor, and the prognosis of patients with osteosarcoma is still unsatisfactory with low survival rates. There are many studies assessing the prognostic role of upregulated p53 in patients presenting osteosarcoma, and there is no consistent finding. To summarize the existing evidence about whether the presence of upregulated p53 was a biomarker of survival in patients with osteosarcoma, we performed a systematic review and meta-analysis of relevant publications. We assessed the effect of upregulated p53 on the 3-year overall survival and the 3-year disease-free survival by calculating the pooled odds ratio (OR) with corresponding 95% confidence interval (95%CI). Fifteen studies with a total of 609 patients with osteosarcoma were finally included into the systematic review and meta-analysis. Compared with osteosarcoma patients with low or undetectable p53, patients with upregulated p53 were obviously associated with decreased 3-year overall survival (OR = 0.29, 95 %CI 0.19-0.43, P < 0.001). In addition, patients with upregulated p53 were obviously associated with decreased 3-year disease-free survival (OR = 0.06, 95 %CI 0.02-0.23, P < 0.001). The results from the systematic review and meta-analysis highlight that p53 is an effective biomarker of survival in patients with osteosarcoma. In addition, more studies with a large sample size are needed to identify the effect of p53 expression in osteosarcoma patients.

Related: Osteosarcoma TP53

Zhao Z, Wu MS, Zou C, et al.
Downregulation of MCT1 inhibits tumor growth, metastasis and enhances chemotherapeutic efficacy in osteosarcoma through regulation of the NF-κB pathway.
Cancer Lett. 2014; 342(1):150-8 [PubMed] Related Publications
Monocarboxylate transporter isoform 1 (MCT1) is an important member of the proton-linked MCT family and has been reported in an array of human cancer cell lines and primary human tumors. MCT1 expression is associated with developing a new therapeutic approach for cancer. In this study, we initially showed that MCT1 is expressed in a variety of human osteosarcoma cell lines. Moreover, we evaluated the therapeutic response of targeting MCT1 using shRNA or MCT1 inhibitor. Inhibiting MCT1 delayed tumor growth in vitro and in vivo, including in an orthotopic model of osteosarcoma. Targeting MCT1 greatly enhanced the sensitivity of human osteosarcoma cells to the chemotherapeutic drugs adriamycin (ADM). In addition, we observed that MCT1 knockdown significantly suppressed the metastatic activity of osteosarcoma, including wound healing, invasion and migration. Further mechanistic studies revealed that the antitumor effects of targeting MCT1 might be related to the NF-κB pathway. Immunochemistry assay showed that MCT1 was an independent positive prognostic marker in osteosarcoma patients. In conclusion, our data, for the first time, demonstrate that MCT1 inhibition has antitumor potential which is associated with the NF-κB pathway, and high MCT1 expression predicates poor overall survival in patients with osteosarcoma.

Related: Signal Transduction

Poos K, Smida J, Nathrath M, et al.
How microRNA and transcription factor co-regulatory networks affect osteosarcoma cell proliferation.
PLoS Comput Biol. 2013; 9(8):e1003210 [PubMed] Article available free on PMC after 01/05/2014 Related Publications
Osteosarcomas (OS) are complex bone tumors with various genomic alterations. These alterations affect the expression and function of several genes due to drastic changes in the underlying gene regulatory network. However, we know little about critical gene regulators and their functional consequences on the pathogenesis of OS. Therefore, we aimed to determine microRNA and transcription factor (TF) co-regulatory networks in OS cell proliferation. Cell proliferation is an essential part in the pathogenesis of OS and deeper understanding of its regulation might help to identify potential therapeutic targets. Based on expression data of OS cell lines divided according to their proliferative activity, we obtained 12 proliferation-related microRNAs and corresponding target genes. Therewith, microRNA and TF co-regulatory networks were generated and analyzed regarding their structure and functional influence. We identified key co-regulators comprising the microRNAs miR-9-5p, miR-138, and miR-214 and the TFs SP1 and MYC in the derived networks. These regulators are implicated in NFKB- and RB1-signaling and focal adhesion processes based on their common or interacting target genes (e.g., CDK6, CTNNB1, E2F4, HES1, ITGA6, NFKB1, NOTCH1, and SIN3A). Thus, we proposed a model of OS cell proliferation which is primarily co-regulated through the interactions of the mentioned microRNA and TF combinations. This study illustrates the benefit of systems biological approaches in the analysis of complex diseases. We integrated experimental data with publicly available information to unravel the coordinated (post)-transcriptional control of microRNAs and TFs to identify potential therapeutic targets in OS. The resulting microRNA and TF co-regulatory networks are publicly available for further exploration to generate or evaluate own hypotheses of the pathogenesis of OS (

Related: Osteosarcoma

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