Primary Bone Tumor In Children Research Articles

Bone deposition, bone resorption, and osteosarcoma

Bone deposition and bone resorption are ongoing dynamic processes, constituting bone remodeling. Some bone tumors, such as osteosarcoma (OS), stimulate focal bone deposition. OS is the most common primary bone tumor in children and young adults. A complex network of genes regulates bone remodeling and alterations in its expression levels can influence the genesis and progression of bone diseases, including OS. We hypothesized that the expression profiles of bone remodeling regulator genes would be correlated with OS biology and clinical features. We used real-time PCR to evaluate the mRNA levels of the tartrate-resistant acid phosphatase (ACP5), colony stimulating factor-1 (CSF1R), bone morphogenetic protein 7 (BMP7), collagen, type XI, alpha 2 (COL11A2), and protein tyrosine phosphatases zeta 1 (PTPRZ1) genes, in 30 OS tumor samples and correlated with clinical and histological data. All genes analyzed, except CSF1R, were differentially expressed when compared with normal bone expression profiles. In our results, OS patients with high levels of COL11A2 mRNA showed worse overall (p = 0.041) and event free survival (p = 0.037). Also, a trend for better overall survival was observed in patients with samples showing higher expression of BMP7 (p = 0.067). COL11A2 overexpression and BMP7 underexpression could collaborate to OS tumor growth, through its central role in bone remodeling process.

Osteosarcoma is characterised by reduced expression of markers of osteoclastogenesis and antigen presentation compared with normal bone

Background:Osteosarcoma (OS) is the most common primary bone tumour in children and adolescents. Patients who respond poorly to chemotherapy have a higher risk of metastatic disease and 5-year survival rates of only 10–20%. Therefore, identifying molecular targets that are specific for OS, or more specifically, metastatic OS, will be critical to the development of new treatment strategies to improve patient outcomes.Methods:We performed a transcriptomic analysis of chemo-naive OS biopsies and non-malignant bone biopsies to identify differentially expressed genes specific to OS, which could provide insight into OS biology and chemoresistance.Results:Statistical analysis of the OS transcriptomes found differential expression of several metallothionein family members, as well as deregulation of genes involved in antigen presentation. Tumours also exhibited significantly increased expression of ID1 and profound down-regulation of S100A8, highlighting their potential as therapeutic targets for OS. Finally, we found a significant correlation between OS and impaired osteoclastogenesis and antigen-presenting activity. The reduced osteoclastogenesis and antigen-presenting activity were more profound in the chemoresistant OS samples.Conclusion:Our results indicate that OS displays gene signatures consistent with decreased antigen-presenting activity, enhanced chemoresistance, and impaired osteoclastogenesis. Moreover, these alterations are more pronounced in chemoresistant OS tumour samples.

Abstract C213: Sorafenib blocks tumor growth, angiogenesis, and metastatic potential in preclinical models of osteosarcoma through the inhibition of ERK1/2, MCL-1, and ezrin pathways

Abstract Osteosarcoma (OS) is the most common primary bone tumor in children and young adults. Despite improved prognosis, metastatic or relapsed OS remains largely incurable and no significant improvement has been observed in the last 20 years. Therefore, the search for alternative agents in OS is mandatory. We explored phospho-ERK 1/2, MCL-1, phospho-Ezrin/Radixin/Moesin (P-ERM) as potential therapeutic targets. The activation of these pathways was shown by immunohistochemistry in about 70% of cases and in all OS cell lines analyzed. Mutational analysis revealed no activating mutations in KRAS. While, BRAF gene was found mutated in 4/30 OS samples from patients. Based on these results we tested the multikinases inhibitor sorafenib (BAY 43-9006) in preclinical models of OS. Sorafenib inhibited OS cell lines proliferation, induced apoptosis and downregulated P-ERK1/2, MCL-1, P-ERM in a dose dependent manner. ERM dephosphorylation is not due to ERK inhibition. The downregulation of MCL-1 increased apoptosis in OS cell lines. In chick embryo chorioallantoic membrane the angiogenesis induced by OS supernatants was blocked by sorafenib treatments. Indeed, sorafenib reduced VEGF and MMP2 production. Sorafenib treatment dramatically reduced tumor volume of OS xenografts and lung metastasis in SCID mice. In conclusion, ERK1/2, MCL-1 and ERM pathways are active in OS. Sorafenib is able to interrupt their routes in vitro and in vivo displaying antitumoral activity, antiangiogenic effect and reducing metastasis colonies formation in lungs. These data support the testing of sorafenib as a potential therapeutic option in metastatic or relapsed OS patients failing standard treatments. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C213.

Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways

BackgroundOsteosarcoma (OS) is the most common primary bone tumour in children and young adults. Despite improved prognosis, metastatic or relapsed OS remains largely incurable and no significant improvement has been observed in the last 20 years. Therefore, the search for alternative agents in OS is mandatory.ResultsWe investigated phospho-ERK 1/2, MCL-1, and phospho-Ezrin/Radixin/Moesin (P-ERM) as potential therapeutic targets in OS. Activation of these pathways was shown by immunohistochemistry in about 70% of cases and in all OS cell lines analyzed. Mutational analysis revealed no activating mutations in KRAS whereas BRAF gene was found to be mutated in 4/30 OS samples from patients. Based on these results we tested the multi-kinase inhibitor sorafenib (BAY 43-9006) in preclinical models of OS. Sorafenib inhibited OS cell line proliferation, induced apoptosis and downregulated P-ERK1/2, MCL-1, and P-ERM in a dose-dependent manner. The dephosphorylation of ERM was not due to ERK inhibition. The downregulation of MCL-1 led to an increase in apoptosis in OS cell lines. In chick embryo chorioallantoic membranes, OS supernatants induced angiogenesis, which was blocked by sorafenib and it was also shown that sorafenib reduced VEGF and MMP2 production. In addition, sorafenib treatment dramatically reduced tumour volume of OS xenografts and lung metastasis in SCID mice.ConclusionIn conclusion, ERK1/2, MCL-1 and ERM pathways are shown to be active in OS. Sorafenib is able to inhibit their signal transduction, both in vitro and in vivo, displaying anti-tumoural activity, anti-angiogenic effects, and reducing metastatic colony formation in lungs. These data support the testing of sorafenib as a potential therapeutic option in metastatic or relapsed OS patients unresponsive to standard treatments.

Statin-Induced Inhibition of 3-Hydroxy-3-Methyl Glutaryl Coenzyme A Reductase Sensitizes Human Osteosarcoma Cells to Anticancer Drugs

Osteosarcoma is the most common primary bone tumor in children and young adults. Resistance to chemotherapeutic drugs is a major problem that is responsible for the failure of treatment. This points to the need for increasing the responsiveness to cytotoxic drugs. We previously showed that lipophilic statins induce apoptosis in human osteosarcoma cells. In this study, we investigated the effects of atorvastatin [(3R,5R)-7[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoïc acid] in combination with chemotherapeutic drugs on human osteosarcoma cell apoptosis, invasion, and migration. We report here that atorvastatin enhances the reduced cell viability induced by the anticancer drugs doxorubicin (Adriamycin; (1S,3S)-amino-3 tridesoxy-2,3,6 alpha-l-lyxo-hexopyranoside glycoloyl-3 trihydroxy-3,5,12 methoxy-10 dioxo-6,11 naphtacenyl-1) and cisplatin in human osteosarcoma cells. In particular, we found that atorvastatin enhances the induction of osteosarcoma cell apoptosis by anticancer drugs. In addition, we show that atorvastatin enhances the inhibitory effect of anticancer drugs on osteosarcoma cell migration. Moreover, atorvastatin and chemotherapeutic drugs had additive inhibitory effects on osteosarcoma cell invasion. In consistent tests, atorvastatin further augmented the reduction of matrix metalloprotease 2 activity induced by doxorubicin or cisplatin in osteosarcoma cells. The results show for the first time that atorvastatin sensitizes osteosarcoma cells to anticancer drugs, resulting in reduced cell viability, migration, and invasion, which suggest a strategy to improve the response to chemotherapy and reduce tumorigenesis in human osteosarcoma.

Therapy for Osteosarcoma

Osteosarcoma is the most common malignant primary bone tumor in children and adolescents. Current optimal treatment for osteosarcoma consists of multi-agent chemotherapy and aggressive surgical resection of all sites of disease involvement. The current national and international cooperative trial for patients with newly diagnosed osteosarcoma builds upon the backbone of cisplatin, doxorubicin, and methotrexate. This protocol is designed to clarify whether (i) the addition of ifosfamide and etoposide to postoperative chemotherapy with cisplatin, doxorubicin, and methotrexate improves the event-free survival and overall survival for patients with resectable osteosarcoma and a poor histologic response to 10 weeks of preoperative chemotherapy; and (ii) the addition of pegylated interferon-alpha-2b as maintenance therapy after postoperative chemotherapy with cisplatin, doxorubicin, and methotrexate improves the event-free survival and overall survival for patients with resectable osteosarcoma and a good histologic response to 10 weeks of preoperative chemotherapy. However, the optimal treatment strategy (or strategies) for patients with relapsed or metastatic disease has yet to be defined. This remains one of the persistent challenges in the treatment of osteosarcoma. Recent therapeutic advances have focused on circumventing chemotherapy resistance mechanisms, incorporation of non-classical agents into upfront therapy, targeting of the tumor micro-environment, and investigating the role of novel delivery mechanisms. In patients with localized disease the 5-year survival rate is at least 70%; patients with metastatic or recurrent disease have <20% chance of long-term survival despite aggressive therapies. These figures have changed little in the past 2 decades. This review focuses on the current therapy for osteosarcoma, and highlights emerging strategies that will hopefully change the outlook for patients with this disease.

Accumulation of Tc-99m DTPA in Ewing Sarcoma

Ewing sarcoma is the second most frequent primary bone tumor in children. The authors present the case of a 15-year-old girl with Ewing sarcoma situated in the right iliac ala. During chemotherapy, dynamic scintigraphy was performed with the use of Tc-99m DTPA to evaluate kidney function. Intensive, unusual accumulation of the radiotracer outside the urinary system around the tumor was seen during examination.

The role of imaging in the staging and treatment planning of primary malignant bone tumors in children

The accurate staging of primary bone tumors in children is critical for treatment planning. Limb salvage operations can now be performed with excellent outcomes in suitable patients. The purpose of this article is to review the current state of imaging techniques and their roles in enabling accurate staging and treatment planning to be performed in pediatric patients with primary bone tumors.

Lower Leg Pain in a 17-Year-Old BoyOrthopaedic-Radiology-Pathology Conference

Lower Leg Pain in a 17-Year-Old BoyOrthopaedic-Radiology-Pathology Conference

Primary Bone Tumors in Children

The combination of clinical information and the findings on conventional radiographs should lead the physician to a narrow differential diagnosis. Before biopsy, appropriate diagnostic and staging studies should be carried out. The biopsy reveals the pathologic diagnosis and a definitive treatment plan then can be instituted. An algorithm is provided for the evaluation and treatment of a child with a suspected bone tumor (Fig. 14).

Adjuvant Arterial Embolization in the Treatment of Benign Primary Bone Tumors in Children

This report presents an initial clinical experience with arterial embolization as adjuvent therapy in the surgical treatment of selected benign primary bone tumors in childhood. Embolization was dramatically effective in 4 children with spinal or pelvic vascular tumors. This technique facilitated local surgical resection and/or curettage. No child had evidence of local recurrence. Three of the 4 children had spinal cord or nerve root compression resulting in various degrees of paralysis prior to surgery. All treated patients had complete recovery from their paralysis. There were no complications of embolization or surgery. The treatment of benign primary bone tumors of the spine and pelvis is immeasurably improved by the adjuvant arterial embolization procedure. The immediate surgical treatment of these difficult tumors now becomes feasible with the greatly diminished blood flow resulting from embolization.

Primary bone tumors in children

Bone tumors in children constitute an unusual, a difficult and an extremely discouraging problem. Early recognition and careful study are necessary prerequisites to proper therapy. The services of a well-trained radiologist are indispensable both for arriving at the diagnosis and often for assisting in the actual treatment. The pathologist also is an invaluable member of the team. The surgeon should freely avail himself of their assistance and the selection of treatment should follow upon a decision in which each has had a voice. While an earlier diagnosis is one of the goals for which we are striving, it should be realized that the earlier the case is seen, the greater are the difficulties of establishing a correct diagnosis. In this connection it is, perhaps, needless to stress the importance of laboratory data which should include a Wassermann, blood chemistry and complete blood count as well as a urinalysis for Bence Jones bodies. Until the happy millenium is reached when the ideal treatment, based upon a knowledge of the underlying etiology of malignant diseases of bone, has been discovered, we must strive for earlier recognition and more prompt and thorough treatment. In this effort the part played by the radiologist is a major one. It is, perhaps, not beyond the realm of possibility that during the next two decades strides will be made by them in the treatment of malignant lesions of bone comparable to those made in the diagnosis during the same period in the immediate past. This, to my mind, is by no means the least of the many glorious achievements of this honored branch of our profession.

Primary Bone Tumors in Children

BONE tumors occur in children with a somewhat greater frequency than has been generally supposed, primary malignant bone tumors occurring rather more frequently in them than in adults. Except for the fact that because of the age factor a less satisfactory history can be elicited in children, there is no material difference between children and adults as regards symptomatology, physical findings, diagnosis, treatment, and prognosis of bone tumors. In 16,000 admissions at the Orthopedic Hospital, 89 bone tumors have been recognized, an incidence of one in 180. To this group of cases were added 28 from the Yale Street Clinic, making a total of 117 cases. Twenty-two, or 18.6 per cent, of these were malignant tumors, while 95, or 81.4 per cent, were benign tumors, the group being divided as follows: The general incidence of bone tumors to admissions has been one tumor to 180 admissions, an incidence of approximately 0.5 per cent. There has been one malignant tumor to 888 admissions. The majority of these were ...