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Fascin-1 enhances experimental osteosarcoma tumor formation and metastasis and is related to poor patient outcome. Fascin-1, a prominent actin-bundling protein, is found to be upregulated in several human carcinomas. While it is accepted that Fascin-1 expression correlates with poor clinical outcome and decreased survival in various carcinomas, its role in sarcoma such as osteosarcoma (OS) remains unknown. In the present study, we evaluated the prognostic value and biological relevance
Mitochondrial genome and functional defects in osteosarcoma are associated with their aggressive phenotype. Osteosarcoma (OSA) is an aggressive mesenchymal tumor of the bone that affects children and occurs spontaneously in dogs. Human and canine OSA share similar clinical, biological and genetic features, which make dogs an excellent comparative model to investigate the etiology and pathogenesis of OSA. Mitochondrial (mt) defects have been reported in many different cancers including OSA
Osteosarcoma after the age of fifty: A clinicopathological study. Osteosarcoma, a primary malignant bone tumor, has a well-recognised double peak of incidence in early adolescence and after 50 years. This study investigates the clinical features and prognostic factors of patients older than 50 years with osteosarcoma.From January 2000 to December 2012, in one bone tumor reference center, 32 patients aged more than 50 years at the diagnosis (mean age: 62.4 years (50-85), sex ratio: 13 males, 19 (...) females) diagnosed with osteosarcoma were included. Patients younger than 50 years at diagnosis or with a non-histologically proved osteosarcoma were excluded. For each patient, we registered medical history, tumor location, systemic and local extension, treatment, and survival.62% were located in the extremities and 28% in the axial skeleton. 6 were secondary sarcomas. Mean delay between first symptoms and biopsy was 7.4 months (range from 0 to 28 months). Ten patients had a systemic osteosarcoma
Surgery and proton beam therapy for mediastinal extraskeletal osteosarcoma. Extraskeletal osteosarcoma (ESOS) arising from the mediastinum is a rare malignant tumor and associated with a poor prognosis. We present the case of a 73-year-old man with a hoarseness. Imaging studies revealed a large calcified tumor of the median mediastinum. Surgery was performed, but complete resection was impossible and about two-thirds of the tumor was excised. The tumor was pathologically diagnosed as ESOS
Genome sequencing analysis of blood cells identifies germline haplotypes strongly associated with drug resistance in osteosarcoma patients. Osteosarcoma is the most common malignant bone tumor in children. Survival remains poor among histologically poor responders, and there is a need to identify them at diagnosis to avoid delivering ineffective therapy. Genetic variation contributes to a wide range of response and toxicity related to chemotherapy. The aim of this study is to use sequencing (...) of blood cells to identify germline haplotypes strongly associated with drug resistance in osteosarcoma patients.We used sequencing data from two patient datasets, from Inova Hospital and the NCI TARGET. We explored the effect of mutation hotspots, in the form of haplotypes, associated with relapse outcome. We then mapped the single nucleotide polymorphisms (SNPs) in these haplotypes to genes and pathways. We also performed a targeted analysis of mutations in Drug Metabolizing Enzymes and Transporter
Interaction between the BAG1S isoform and HSP70 mediates the stability of anti-apoptotic proteins and the survival of osteosarcoma cells expressing oncogenic MYC. The oncoprotein MYC has the dual capacity to drive cell cycle progression or induce apoptosis, depending on the cellular context. BAG1 was previously identified as a transcriptional target of MYC that functions as a critical determinant of this cell fate decision. The BAG1 protein is expressed as multiple isoforms, each having (...) an array of distinct biochemical functions; however, the specific effector function of BAG1 that directs MYC-dependent cell survival has not been defined.In our studies the human osteosarcoma line U2OS expressing a conditional MYC-ER allele was used to induce oncogenic levels of MYC. We interrogated MYC-driven survival processes by modifying BAG1 protein expression. The function of the separate BAG1 isoforms was investigated by depleting cells of endogenous BAG1 and reintroducing the distinct isoforms
Effectiveness of 18F-FDG PET/CT in the diagnosis and staging of osteosarcoma: a meta-analysis of 26 studies. Multiple trials have attempted to assess the diagnostic value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in osteosarcoma with results remaining inconclusive. This study aims to investigate the effectiveness of 18F-FDG PET and PET/CT in the diagnosis, staging, recurrence and metastasis formation observations of osteosarcoma (...) through systematic review followed by meta-analysis.Three electronic databases, Medline/PubMed, Embase and the Cochrane Library were utilized in this study. Eligible studies that assessed the performance of 18F-FDG PET/CT for the diagnosis, staging, restaging and recurrence monitoring of osteosarcoma were retrieved utilizing specific search criteria. After screening and diluting out the non-conforming articles, all relevant articles and their data were identified and extracted to calculate the summary
Nomograms predicting overall survival and cancer-specific survival in osteosarcoma patients (STROBE). The aim of this study was to develop nomograms to predict long-term overall survival and cancer-specific survival of patients with osteosarcoma.We carried out univariate and multivariate analyses and set up nomograms predicting survival outcome using osteosarcoma patient data collected from the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute (2004-2011 (...) , n = 1426). The patients were divided into a training cohort (2004-2008, n = 863) and a validation cohort (2009-2011, n = 563), and the mean follow-up was 55 months.In the training cohort, 304 patients (35.2%) died from osteosarcoma and 91 (10.5%) died from other causes. In the validation cohort, 155 patients (27.5%) died from osteosarcoma and (12.3%) died from other causes. Nomograms predicting overall survival (OS) and cancer-specific survival (CSS) were developed according to 6
Sarcome-13/OS2016 trial protocol: a multicentre, randomised, open-label, phase II trial of mifamurtide combined with postoperative chemotherapy for patients with newly diagnosed high-risk osteosarcoma. The controversial results on the mifamurtide efficacy associated with chemotherapy, issued from the American INT-0133-study, in localised osteosarcomas, and the underpowered analysis performed separately in metastatic patients, should be clarified to homogenise international use of this promising (...) drug. The European Commission has granted a marketing authorisation to mifamurtide combined with postoperative chemotherapy in localised osteosarcomas but not in metastatic patients, while the Food and Drug Administration (FDA) has denied this authorisation.Sarcome-13/OS2016 trial is a multicentre randomised open-label phase II trial evaluating the survival benefit of mifamurtide administered during 36 weeks in combination with postoperative chemotherapy versus chemotherapy alone, in patients >2
Clinical genomic sequencing of pediatric and adult osteosarcoma reveals distinct molecular subsets with potentially targetable alterations. While multimodal chemotherapy has improved outcomes for patients with osteosarcoma (OS), the prognosis for patients who present with metastatic and/or recurrent disease remains poor. In this study, we sought to define how often clinical genomic sequencing of OS samples could identify potentially actionable alterations.We analyzed genomic data from 71 OS
Methotrexate, doxorubicin, and cisplatinum regimen is still the preferred option for osteosarcoma chemotherapy: A meta-analysis and clinical observation. We designed the study to investigate whether methotrexate, doxorubicin, and cisplatinum (MAP) chemotherapy strategy was still the preferred option for the survival of osteosarcoma patients.We collected some trials of osteosarcoma to make a meta-analysis first. Then, we retrospectively collected data from 115 patients with osteosarcoma (...) of clinical data.MAP regimen remains the preferred option for osteosarcoma chemotherapy.
Efficacy and safety of apatinib in treatment of osteosarcoma after failed standard multimodal therapy: An observational study. Recently, apatinib has been shown to be effective in treating sarcoma. This study aimed to assess the safety and efficacy of apatinib in the treatment of patients with osteosarcoma after failed of standard multimodal therapy and to compare the therapeutic effects of apatinib on osteosarcoma between high-dose group and low-dose group.A total of 27 patients (...) with osteosarcoma who received apatinib between January 2016 and August 2017 were retrospectively reviewed. Among the 27 patients, the objective response rate (ORR) and the disease control rate (DCR) were 25.93% and 66.67%, respectively. The median of progression-free survival (m-PFS) was 3.5 months (95% confidence interval [CI], 2.5-4.8 months), and the median of overall survival (m-OS) was 9.5 months (95% CI, 7.8-10.5 months). There was no statistically significant difference in ORR (36.36% vs 18.75%), DCR
Development and validation of a nomogram for osteosarcoma-specific survival: A population-based study. This study aimed to establish a comprehensive prognostic system for osteosarcoma based on a large population database with high quality.The Surveillance, Epidemiology, and End Results (SEER) Program database was used to identify patients with osteosarcoma from 1973 to 2015. Multivariate analysis was performed to screen statistically significant variables. A nomogram was constructed by R (...) software to predict the 3-, 5- and 10-year survival rates. Predictive abilities were compared by C-indexes, calibration plots, integrated discrimination improvement (IDI), net reclassification improvement (NRI), as well as decision curve analysis (DCA).In total, 4505 osteosarcoma patients were identified. They were divided into training (70%, n = 3153) and validating (30%, n = 1352) groups. Multivariate analyses identified independent predictors. Subsequently, the nomogram system of a new model
Method to measure the mismatch between target and achieved received dose intensity of chemotherapy in cancer trials: a retrospective analysis of the MRC BO06 trial in osteosarcoma. In cancer studies, the target received dose intensity (tRDI) for any regimen, the intended dose and time for the regimen, is commonly taken as a proxy for achieved RDI (aRDI), the actual individual dose and time for the regimen. Evaluating tRDI/aRDI mismatches is crucial to assess study results whenever patients (...) are stratified on allocated regimen. The manuscript develops a novel methodology to highlight and evaluate tRDI/aRDI mismatches.Retrospective analysis of a randomised controlled trial, MRC BO06 (EORTC 80931).Population-based study but proposed methodology can be applied to other trial designs.A total of 497 patients with resectable high-grade osteosarcoma, of which 19 were excluded because chemotherapy was not started or the estimated dose was abnormally high (>1.25 × prescribed dose).Two regimens
Novel therapeutic strategies for spinal osteosarcomas. At the dawn of the third millennium, cancer has become the bane of twenty-first century man, and remains a predominant public health burden, affecting welfare and life expectancy globally. Spinal osteogenic sarcoma, a primary spinal malignant tumor, is a rare and challenging neoplastic disease to treat. After the conventional therapeutic modalities of chemotherapy, radiation and surgery have been exhausted, there is currently no available (...) alternative therapy in managing cases of spinal osteosarcoma. The defining signatures of tumor survival are characterised by cancer cell ability to stonewall immunogenic attrition and apoptosis by various means. Some of these biomarkers, namely immune-checkpoints, have recently been exploited as druggable targets in osteosarcoma and many other different cancers. These promising strides made by the use of reinvigorated immunotherapeutic approaches may lead to significant reduction in spinal osteosarcoma
Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma. SARC024 is a phase II clinical trial of the multikinase inhibitor regorafenib in specific sarcoma subtypes, including advanced osteosarcoma. We hypothesized that regorafenib would improve progression-free survival (PFS) in patients with sarcoma and report the results of the osteosarcoma cohort.This trial enrolled patients with progressive metastatic osteosarcoma with measurable disease by RECIST who (...) survival. Fourteen (64%) of 22 patients initially randomly assigned to regorafenib experienced grade 3 to 4 events attributed to treatment, including one grade 4 colonic perforation.The study met its primary end point, demonstrating activity of regorafenib in patients with progressive metastatic osteosarcoma. No new safety signals were observed. Regorafenib should be considered a treatment option for patients with relapsed metastatic osteosarcoma.
Phase II trial of the glycoprotein non-metastatic B-targeted antibody-drug conjugate, glembatumumab vedotin (CDX-011), in recurrent osteosarcoma AOST1521: A report from the Children's Oncology Group. The prognosis is poor for children and adolescents with recurrent osteosarcoma (OS). Glycoprotein non-metastatic B (gpNMB) is a glycoprotein highly expressed in OS cells. We conducted a phase II study of glembatumumab vedotin (GV), a fully human IgG2 monoclonal antibody (CR011) against gpNMB
Common genetic variation and risk of osteosarcoma in a multi-ethnic pediatric and adolescent population. Osteosarcoma, a malignant primary bone tumor most commonly diagnosed in children and adolescents, has a poorly understood genetic etiology. Genome-wide association studies (GWAS) and candidate-gene analyses have identified putative risk variants in subjects of European ancestry. However, despite higher incidence among African-American and Hispanic children, little is known regarding common (...) heritable variation that contributes to osteosarcoma incidence and clinical presentation across racial/ethnic groups. In a multi-ethnic sample of non-Hispanic white, Hispanic, African-American and Asian/Pacific Islander children (537 cases, 2165 controls), we performed association analyses assessing previously-reported loci for osteosarcoma risk and metastasis, including meta-analysis across racial/ethnic groups. We also assessed a previously described association between genetic predisposition
Improving the efficacy of osteosarcoma therapy: combining drugs that turn cancer cell 'don't eat me' signals off and 'eat me' signals on. The long-term survival of osteosarcoma patients with metastatic or recurrent disease remains dismal, and new therapeutic options are urgently needed. The purpose of our study was to compare the efficacy of CD47 mAb plus doxorubicin combination therapy in mouse models of osteosarcoma with CD47 mAb and doxorubicin monotherapy. Forty-eight NOD scid gamma (NSG (...) underwent survival analyses with Kaplan-Meier curves and a log-rank (Mantel-Cox) test. Intratibial osteosarcomas demonstrated significantly stronger ferumoxytol enhancement and significantly increased TAM quantities after CD47 mAb plus doxorubicin combination therapy compared to CD47 mAb (P = 0.02) and doxorubicin monotherapy (P = 0.001). Tumor-bearing mice treated with CD47 mAb plus doxorubicin combination therapy demonstrated significantly reduced tumor size and prolonged survival compared to control