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The effect of nivolumab and the relation between bone response and tumor control in patients with non-small-cell lung cancer (NSCLC) with bone metastases are not clear. The outcome of nivolumab monotherapy was investigated, and whether the response of bone metastases is useful as an early predictor of tumor control in patients with NSCLC with bone metastases was examined. The participants included 15 patients who received nivolumab monotherapy for NSCLC with bone metastases in our institution between 2015 and 2017. Tumor control was defined using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST1.1). Response of bone metastases was assessed by the MD Anderson response criteria (MDA criteria). Responses according to RECIST1.1 and the MDA criteria were classified as responder (complete response or partial response) and non-responder [progressive disease (PD) or stable disease]. Progression-free survival (PFS) was investigated using the Kaplan-Meier method. With RECIST1.1, the overall response rate was 20%. Multivariate analysis showed that the MDA criteria were the only risk factor for patients with PD (RECIST1.1). Median PFS was 1.9 months, with PFS of 20% at 6 months. Univariate analysis showed that being a non-responder according to the MDA criteria was the only risk factor for PFS. In patients who were responders (MDA criteria) within 3 months, PFS was 83 and 50% at 3 and 6 months, respectively, though all non-responder (MDA criteria) patients converted to PD (RECIST1.1) within 3 months. Response according to RECIST1.1 was significantly correlated with response according to the MDA criteria (P<0.05). In patients who were both responders according to RECIST1.1 and the MDA criteria, time to response with the MDA criteria (1.4–2.0 months) was earlier than with RECIST1.1 (2.8–3.0 months) in all patients. In conclusion, application of the MDA criteria within 2 months of nivolumab monotherapy is useful for early prediction of response and prognosis in patients with NSCLC with bone metastases. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is the most commonly diagnosed malignant cancer of bone that occurs in adolescents and children. Mounting number of studies have indicated that miRNAs are increasingly playing fundamental roles in OS development. Thus, the biological function of miR-429 in OS progression was explored. The results of RT-qPCR revealed that miR-429 was downregulated in OS tissues and OS cell lines (MG-63, U2OS, Saos-2) while homeobox A9 (HOXA9) was markedly increased. Moreover, HOXA9 was confirmed as a direct target of miR-429 by using luciferase reporter assay. It was identified that miR-429 exhibited a suppressive effect on OS progression while HOXA9 showed the oncogenic function in OS progression by using MTT and Transwell assays. More importantly, rescue assays manifested that HOXA9 can partially overturn the suppressive effect of miR-429 on OS. Overexpression of miR-429 inhibited the activation of Wnt/β-catenin signaling pathway. In conclusion, miR-429 suppressed OS progression by targeting HOXA9 through Wnt/β-catenin pathway. [ABSTRACT FROM AUTHOR]

The present study investigated the clinical significance afforded by locoregional surgery in improving the prognosis of primary metastatic testicular cancer (pMTC). The population-based Surveillance, Epidemiology and End Results database was used as the primary source of data in the present study. Stratification analysis was employed to identify the effects of testicular surgery on testicular cancer-specific survival and overall survival. Propensity score matching and Cox regression models were then employed to find and evaluate the extent of improvements to the survival of patients with pMTC by testicular surgery. The median testicular cancer-specific survival and overall survival in the surgery group were 10% higher than those in the group without surgery. Testicular surgery was demonstrated to have provided a survival advantage for patients with a single metastasis in the bone or brain, but not in the liver or lung. When combined with radiotherapy and chemotherapy, surgery significantly improved the survival of patients. However, according to the surgical outcome based on molecular subtypes, when deciding on the surgery for patients with metastatic testicular cancer, only human chorionic gonadotropin and lactate dehydrogenase, and not α-fetoprotein should be considered. Surgery serves a significant role in the management of non-seminoma, whereas its role in the management of seminoma is far more limited. The effects of locoregional surgery have been neglected when treating patients with pMTC. Surgical procedures should be considered more seriously when planning combination treatments for patients with pMTC with a single bone or brain metastasis. [ABSTRACT FROM AUTHOR]

Primary thoracic bone tumors are relatively rare. The most common type is chondrosarcoma, accounting for up to 48% of all cases. Patients with primary thoracic bone tumors commonly present with atypical thoracic pain or a solitary palpable chest mass, which gradually develops over months to years. The bones most often affected are the ribs, scapula, costochondral junctions and the sternum. The present study presents a case of a 79 year old previous transplant recipient with a large intra-abdominally expanding chondrosarcoma originating from the left lower thoracic cage and associated vague abdomdinal symptoms. Early recognition and awareness of atypical presentations of this disease are important in to appropriately guide diagnostic evaluation and therapeutic procedures. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most common type of malignant bone tumor, which has an overall survival rate of only 15-30%. The present study aimed to investigate the effects of 15-hydroxy-6α,12-epoxy-7β,10αH,11βH-spiroax-4-ene-12-one (HESEO), a compound extracted from the endophytic fungus Penicillium sp. FJ-1 isolated from Avicenniamarina, on the proliferation of osteosarcoma cells and to explore its underlying mechanisms of action. Cell number was counted to measure the cell proliferation. JC-1 reagent was used to measure mitochondrial membrane potential. ELISA was used to measure the cytochrome c level and caspase activities. Apoptosis was detected by Annexin V-Propidium Iodide staining. Gene and protein expression were measured by reverse-transcription-PCR and western blot analysis, respectively. Additionally, the anti-tumor effects of HESEO were explored within a syngeneic osteosarcoma tumor model. The results suggested that HESEO significantly inhibited the proliferation of osteosarcoma cells and induced apoptosis of MG-63 cells, evidenced by their decreased mitochondrial membrane potential, and increased cytochrome c release, caspase activities and percentage of apoptotic cells. In addition, HESEO increased the expression of pro-apoptotic genes and proteins compared with control cells. The results indicated that HESEO may act through increasing p53 upregulated modulator of apoptosis expression. Furthermore, HESEO treatment significantly increased the survival time and decreased the tumor burden of osteosarcoma tumor-bearing mice compared with vehicle treatment. Furthermore, combined treatment with HESEO enhanced the effects of the chemotherapeutic agent methotrexate on a lung metastasis osteosarcoma model. These data suggested that HESEO could be developed as a potential anti-tumor agent against osteosarcoma. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is a primary malignant bone tumor that predominantly occurs in adolescents. Different types of OS tumor are highly malignant, associated with a poor prognosis and are invasive with blood-vessel dissemination characteristics, thus affected patients are prone to early lung metastasis. MicroRNAs (miRNAs/miR) are small non-coding RNA molecules that act as oncogenes or tumor suppressors during tumor development. The present study investigated the role of miR-206 in OS development. Bioinformatics analysis demonstrated that miR-206 was upregulated in OS and thus may serve as a risk factor for cancer prognosis. Subsequently, in response to miR-206 overexpression, differentially expressed genes were screened and analyzed using the Database for Annotation, Visualization and Integrated Discovery, Gene Ontology enrichment analysis, the Kyoto Encyclopedia of Genes and Genomes pathways and protein-protein interaction network construction, in order to identify key miR-206 targets. The results demonstrated that high miR-206 expression inhibited OS cell proliferation, which was associated with a good patient prognosis. Thus, miR-206 may serve as a potential target for OS treatment, in order to improve early disease diagnosis. [ABSTRACT FROM AUTHOR]

Bone metastasis during the early stages of gastric cancer is rare, and synchronous bone metastasis is even less common. The present report outlines a case of a small early gastric cancer, which was detected due to bone metastasis. A 63-year-old man was referred to Fukuyama Medical Center with back pain and anorexia of 2 weeks' evolution. MRI revealed multiple metastatic lesions in the thoracic and spinal bone. Fluorodeoxyglucose positron emission tomography revealed focal uptake in the lesser curvature of the stomach and in the spinal bone, pelvic and thigh bone, but uptake was not detected in the stomach. Esophagogastroduodenoscopy revealed a 10 mm slightly elevated lesion with a central depression in the middle-third of the stomach. Endoscopic ultrasonography confirmed that the tumor was confined to the mucosa. A biopsy specimen acquired from the gastric lesion indicated signet-ring cell carcinoma, and the specimen acquired from the lumbar spine revealed cell aggregation such as that found in signet-ring cell carcinoma. The patient received first-line chemotherapy with S-1 and cisplatin, and second-line chemotherapy with nab-paclitaxel. However, the patient died 120 days after consultation at Fukuyama Medical Center. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most common type of malignant bone cancer and results in cancer-related deaths among adolescents. Alantolactone (ALT) demonstrates antitumor properties in various diseases; however, its potential role in osteosarcoma is relatively unclear. The aim of the present study was to evaluate the effect of ALT on osteosarcoma. ALT significantly decreased the viability of U2OS and HOS osteosarcoma cell lines. Cells flow cytometry assay and Hoechst 33258 staining assay revealed that ALT significantly increased the proportion of apoptotic U2OS cells. In addition, wound healing and Transwell invasion assays demonstrated that the invasion and migration of osteosarcoma were markedly reduced upon ALT treatment. It was hypothesized that the antitumor functions of ALT are mediated through inhibition of the PI3K/AKT signaling pathway. In conclusion, the results of the present study confirmed the inhibition of ALT on osteosarcoma cells via downregulation of PI3K/AKT signaling pathways, suggesting ALT as a potential therapeutic candidate for osteosarcoma. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is the most common type of primary malignant bone tumor, which has a high incidence rate in children and adolescents. This research aims to reveal the role of long intergenic non-protein coding RNA 00460 (LINC00460) in OS by the loss-of-function experiment. LINC00460 is involved in the development of multiple types of tumor, but the role of LINC00460 in OS is unclear. To discover more effective molecular targets for the treatment of OS, the association between LINC00460 and OS prognosis was analyzed using the Gene Expression Profiling Interactive Analysis database. Additionally, small interfering RNA was used to knockdown LINC00460 gene expression in vitro to verify its biological effects on the viability, invasive and migratory potential of OS cells. LINC00460 knockdown significantly reduced the viability of OS cells and initiated cell cycle arrest within the G0/G1 phase through the decreased expression of cyclin D1 and CDK4/CDK6. In addition, LINC00460 knockdown promoted apoptosis of OS cells, and inhibited the migratory and invasive abilities of OS cells through the inhibition of the epithelial-mesenchymal transition pathway. In conclusion, the present study reported that LINC00460 may predict OS prognosis, and may serve an important role in mediating the viability, invasive and migratory potential of OS cells. Based on these findings, LINC00460 demonstrated promising potential as a future therapeutic target for OS treatment. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is a bone tumor of mesenchymal origin, most frequently occurring during the rapid growth phase of long bones, and usually located in the epiphyseal growth plates of the femur or the tibia. Its most common feature is genome disorganization, aneuploidy with chromosomal alterations, deregulation of tumor suppressor genes and of the cell cycle, and an absence of DNA repair. This suggests the involvement of surveillance failures, DNA repair or apoptosis control during osteogenesis, allowing the survival of cells which have undergone alterations during differentiation. Epigenetic events, including DNA methylation, histone modifications, nucleosome remodeling and expression of non-coding RNAs have been identified as possible risk factors for the tumor. It has been reported that p53 target genes or those genes that have their activity modulated by p53, in addition to other tumor suppressor genes, are silenced in OS-derived cell lines by hypermethylation of their promoters. In osteogenesis, osteoblasts are formed from pluripotent mesenchymal cells, with potential for self-renewal, proliferation and differentiation into various cell types. This involves complex signaling pathways and multiple factors. Any disturbance in this process can cause deregulation of the differentiation and proliferation of these cells, leading to the malignant phenotype. Therefore, the origin of OS seems to be multifactorial, involving the deregulation of differentiation of mesenchymal cells and tumor suppressor genes, activation of oncogenes, epigenetic events and the production of cytokines. [ABSTRACT FROM AUTHOR]

There have been few reports on bone metastases (BMs) from esophageal cancer (EC). The aim of the present study was to investigate the clinicopathological features and prognostic factors in patients with EC with BMs. The present study retrospectively collected data from 58 patients with BMs from EC who were treated at our institution between 2007 and 2016. Patient, tumor and BM-associated characteristics were analyzed. Kaplan-Meier survival curves were constructed and analyzed using the univariate log-rank test. Multivariate analyses were conducted using the Cox proportional hazards model. The median patient age was 67 years (range, 39–84 years). Multiple BMs were detected in 38 patients (65.5%) and 52 patients (89.7%) exhibited osteolytic BMs. Skeletal-related events (SREs) occurred in 53 patients (91.4%). The one-year overall survival (OS) was 25.3%, and the median OS was 5 months (range, 0–54). Univariate analyses revealed that performance status, visceral or brain metastasis, serum carcinoembryonic antigen (CEA), C-reactive protein, albumin level, and receipt of chemotherapy following BM diagnosis were significantly associated with OS. Multivariate analyses of these factors demonstrated that higher serum CEA levels and no chemotherapy were significant risk factors for poor OS. Multiple osteolytic BMs are frequently observed in patients with EC with BMs, and SREs commonly occur. The prognoses of patients with EC with BMs are poor, but chemotherapy administration following the BM diagnosis should confer a survival benefit. [ABSTRACT FROM AUTHOR]

I-125 seed therapy has been developed and used for the treatment of numerous types of malignancies. It has been suggested that post-implant dosimetry deviates from pre-implant treatment planning; however, to the best of our knowledge, very few studies to date have investigated this discrepancy. In the present study, 11 patients with metastatic spinal tumors, who were treated with I-125 seed brachytherapy, were assessed. Pre- and post-implant dosimetry were compared by assessing: Tumor volume, dose distributions and dose volume histograms. The average doses delivered to 90% of the target volume (D90) in the pre-implant planning images of the spine was 119.07 Gy compared with 94.15 Gy in the post-implant dosimetry (P<0.05). The average V100 in the pre-implant planning images of the spine was 97.85% (range, 96.50–99.80%), compared with 84.46% (range, 66.40–96.70%) in the post-implant dosimetry, of the prescribed doses (P<0.05). Furthermore, both the number of needles and the Dmax of the cord differed between the two groups. Nevertheless, the mean gross tumor volume, the number of seeds, and the V150 and V200 were similar between the two groups. The results of the present study suggest that metastatic spinal tumors of the bone received a lower dose than the pre-implant planned dose coverage in I-125 seed brachytherapy. [ABSTRACT FROM AUTHOR]

Bone cancer pain (BCP) is a severe complication of advanced bone cancer. Although cannabinoid receptor 2 (CB2) agonists may have an analgesic effect, the underlying mechanism remains unclear. CB2 serves a protective role in various pathological states through the activation of autophagy. Therefore, the present study aimed to determine whether the analgesic effects of the selective CB2 agonist JWH015 was mediated by the activation of autophagy in BCP. BCP was induced by the intra-femur implantation of NCTC2472 fibrosarcoma cells in C3H/HeN mice. The pain behaviors were assessed on the following postoperative days. The selective CB2 agonist JWH015 (1 and 2 µg) was intrathecally administered on day 14 following implantation. AM630 (1 µg), a CB2 antagonist, was injected 30 min before JWH015 administration. Lipopolysaccharide (LPS; 100 nM)-stimulated primary neurons were treated with JWH015 (1 µM) and AM630 (1 µM) to further verify the mechanism by which CB2 affects autophagy. The results demonstrated that autophagy flux was impaired in spinal neurons during BCP, as indicated by the increased ratio of microtubule-associated protein 1 light chain 3β (LC3B)-II/LC3B-I and increased expression of p62. Intrathecal administration of JWH015 attenuated BCP, which was accompanied by the amelioration of impaired autophagy flux (decreased LC3B-II/LC3B-I ratio and decreased p62expression). In addition, the activation of glia cells and upregulation of the glia-derived inflammatory mediators, interleukin (IL)-1β and IL-6 were suppressed by JWH015. In LPS-stimulated primary neurons, IL-1β and IL-6 were increased, and autophagy flux was impaired; whereas treatment with JWH015 decreased the expression of IL-1β and IL-6, LC3B-II/LC3B-I ratio and expression of p62. These effects were by pretreatment with the CB2-selective antagonist AM630. The results of the present study suggested that the impairment of autophagy flux was induced by glia-derived inflammatory mediators in spinal neurons. Intrathecal administration of the selective CB2 agonist JWH015 ameliorated autophagy flux through the downregulation of IL-1β and IL-6 and attenuated BCP. [ABSTRACT FROM AUTHOR]

Ewing's sarcoma (ES) is the second most common bone tumor among children and adolescents worldwide. However, the genes and signaling pathways involved in ES tumorigenesis and progression remain unclear. The present study used two gene-expression profile datasets (GSE17674 and GSE31215) to elucidate key potential candidate genes and pathways in ES. Differentially expressed genes (DEGs) were identified and a functional enrichment analysis was performed. A protein-protein interaction (PPI) network was constructed, and the most significant module in the PPI network was selected from the Search Tool for the Retrieval of Interacting Genes/Proteins database. A total of 278 genes were identified by comparing the tumor samples with non-cancerous samples; these included 272 upregulated and 6 downregulated genes. The pathway analysis demonstrated significant enrichment in the positive regulation of transcription in the DEGs coding for RNA polymerase II promoter, plasma membrane and chromatin binding pathways in cancer in general. There were 269 nodes and 292 edges in the PPI network. Finally, MYC, IGF1, OAS1, EZH2 and ISG15 were identified as the hub genes according to the degree levels. The survival analysis revealed that EZH2 is associated with a poor prognosis in patients with ES. In conclusion, the DEGs, associated pathways and hub genes identified in the present study help elucidate the underlying molecular mechanisms of ES carcinogenesis and progression, and provide potential molecular targets and biomarkers for ES. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is the most common type of bone cancer in children and adolescents, and has a poor prognosis. Previous studies have demonstrated that a number of microRNAs (miRNAs) were deregulated in OS, and that the expression of certain miRNAs was correlated with the stage of OS. Therefore, miRNAs may serve a role as a diagnostic and prognostic biomarker of OS. miRNA and mRNA integrated analysis of public expression profiles in the Gene Expression Omnibus database for OS was performed, and the regulated targets of miRNA in OS were predicted. Next, the regulatory network of miRNAs/genes was constructed and verified by reverse transcription-quantitative polymerase chain reaction in tissues and MG-63 cell lines. Two miRNA expression profiling studies and four eligible mRNA expression profiling studies were selected. Ten upregulated miRNAs, 5 downregulated miRNAs and 5 DGEs were identified in OS compared with normal tissues. hsa-miR-346 was inversely correlated with the target gene c-FLIP, which was consistent with the results of integrated analysis. In vitro, pre-miRNA-346 can downregulate the protein expression of c-FLIP, while not changing the mRNA level of c-FLIP. In the regulatory network, hsa-miR-346 and its target gene, c-FLIP, can be used as biomarkers for an earlier diagnosis of OS. [ABSTRACT FROM AUTHOR]

Bisphosphonates (Bps) inhibit the maturation of osteoclasts and suppress the adhesion of cancer cells to the bone matrix. They are recommended as the standard treatment for tumors exhibiting bone metastasis (BM). However, whether Bps can improve the prognosis of patients with tyrosine kinase inhibitor (TKI)-treated non-small cell lung cancer (NSCLC) exhibiting BM remains unclear. A total of 129 patients with NSCLC initially diagnosed with BM at The First Affiliated Hospital of Sun Yat-Sen University (Guangzhou, China) between January 2005 and December 2017 were analyzed in the present retrospective study. Median progression free survival (mPFS) time, median bone metastasis overall survival (mBM-OS) time and bone-associated progression-free survival were analyzed. Among the 129 patients, patients treated with Bps experienced significantly prolonged PFS time [mPFS: 7.1 vs. 5.1 months; hazard ratio (HR), 0.51; confidence interval (CI), 0.30–0.87; P=0.0114] in comparison with patients not treated with Bps. Of the 49 patients treated with frontline TKIs (EGFR TKIs or ALK TKI), 32 received Bps at the same time, while 17 patients received TKIs alone. The results revealed that mPFS time was significantly greater in the TKIs plus Bps group than in the TKIs alone group (mPFS: 11.2 vs. 6.9 months; HR, 0.13; CI, 0.05–0.35; P<0.0001). Significantly prolonged BM-OS time was also observed in the combination group in comparison with the TKIs alone group (mBM-OS: 31 vs. 22 months; HR, 0.31; CI, 0.10–0.96; P=0.0413). The present study demonstrated that among the patients who received TKIs (EGFR TKIs or ALK TKIs), those who also received Bps experienced significantly longer PFS time and tended to exhibit significantly improved BM-OS time, which indicated that Bps should be added to the treatment regimen of patients with NSCLC exhibiting genetic mutations and bone metastasis who have been prescribed TKIs (EGFR TKIs or ALK TKIs). [ABSTRACT FROM AUTHOR]

Skeletal-related events (SREs) may occur at the time of first diagnosis in 20–30% of lung cancer patients with bone metastases. Several clinical trials have shown that zoledronic acid (ZA) is effective for decreasing SREs. The main objective of the present study was to discuss clinical data of ZA and compare the frequency of SREs with previous reports. All patients with non-small-cell lung cancer (NSCLC) with metastatic bone disease who were administered ZA at least twice between January 2008 and December 2009 were eligible for inclusion in the study. In total, 198 consecutive patients were identified. The median duration of ZA administration was 106 days [95% confidence interval (CI), 92–133 days], and the median number of ZA administrations was 4 (range, 2–41). The median time to first SRE in patients who experienced SRE following ZA treatment was 202 days (95% CI, 156–264 days). Among the 78 patients who had already experienced SRE prior to ZA treatment, 35 (45%) experienced SRE subsequently after starting ZA treatment. On the other hand, among the 120 patients without a history of SRE before starting ZA treatment, 42 (35%) experienced SRE after the start of ZA administration (P=0.16). No osteonecrosis of the jaw (ONJ) was reported in any of the patients. The present study revealed that ZA had a certain level of efficacy regardless of the presence or absence of prior SREs. However, the duration of ZA therapy was short in this study; further accumulation of data on the long-term prognosis and incidence rates of ONJ and other late complications of ZA therapy seems to be particularly important. [ABSTRACT FROM AUTHOR]

Annexin A3 (ANXA3) is highly expressed in different types of cancers, but the impact of ANXA3 in bone tumors is still not clear. In the present study, the expression of ANXA3 in osteosarcoma cells was first confirmed by cellular immunofluorescence. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were used to detect the expression of ANXA3 in osteoblasts in the osteosarcoma cell lines U2OS and HOS. Furthermore, small interfering (si)-RNA were transfected into U2OS and HOS cells via a liposome-mediated method. Then once ANXA3 had been successfully downregulated in U2OS and HOS cells, the cells were collected and total protein was extracted after 48 h of transfection. Western blot analysis was used to confirm successful ANXA3 transfection into osteosarcoma cells and the apoptotic rate of HOS and U2OS was detected by flow cytometry. The expression of ANXA3 in the osteosarcoma cell lines HOS and U2OS were first observed by confocal laser scanning microscopy, and was then detected by RT-qPCR and western blotting. The mRNA and protein levels of ANXA3 in the osteosarcoma cell lines HOS and U2OS were significantly increased compared with osteoblasts, particularly in HOS cells. When siRNA was transfected into HOS and U2OS cells, the protein expression level of ANXA3 was measured via western blotting. The results indicated that the expression of ANXA3 was significantly decreased. In addition, to determine whether ANXA3 knockdown induced cell apoptosis, the present study analyzed the apoptotic rate by flow cytometry. The results revealed that ANXA3 knockdown markedly increased HOS and U2OS cell apoptosis. To the best of our knowledge, the present study is the first to confirm that ANXA3 is highly expressed in the osteosarcoma cell lines HOS and U2OS. In addition, downregulation of ANXA3 expression in HOS and U2OS cells could increase apoptotic ability. [ABSTRACT FROM AUTHOR]

Short-term efficacy and safety of magnetic resonance-guided focused ultrasound surgery (MRgFUS) for analgesia in children with metastatic bone tumors were studied. Thirty children with pediatric bone metastases admitted to Jinan Maternity and Child Care Hospital from March 2015 to March 2018 and who received MRgFUS treatment of the bone metastasis lesions were collected. The postoperative efficacy was assessed. The observation indicators included the Numerical Rating Scale (NRS) scores, European Organization for Research and Treatment of Cancer (EORTC) and Quality of Life Questionnaire (QLQ) scores before surgery, and 1 week, 1, 2, and 3 months after surgery and the Karnofsky Performance Status (KPS) scores before surgery, and 1 week and 3 months after surgery. The adverse reactions and medications of the children after the surgery were also under observation. NRS and VAS scores of all different observation time-points after surgery were statistically lower than those before surgery (P<0.05), and the NRS scores and Visual Analog Scale (VAS) scores 3 months after surgery were lower than those 1 week after surgery (P<0.05). Compared with the preoperative conditions, the QLQ-C30 scores of terms like physical function, cognitive function, nausea and vomiting, and degree of pain 1 week, 1, 2, and 3 months after surgery were decreased, and the clinical symptoms of the children were relieved (P<0.05). There was a statistical difference between the total QLQ-C30 scores 3 months after operation and the total QLQ-C30 scores 3 months before operation (P<0.05). No serious adverse reactions related to treatment were reported, and the application of analgesics was reduced. MRgFUS relieves bone metastasis pain in children with good curative effect and high safety. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most common type of primary malignant bone tumor in children and young adults. However, primary osteosarcoma in elderly patients is rare. The present study reports 3 cases of advanced osteosarcoma in elderly patients. The pathological findings in all 3 cases confirmed the diagnosis of primary osteosarcoma. Notably, each patient received different treatment options. Chemoradiotherapy was recommended in case 1 due to the age of the patient. However, the patient requested to be discharged and was lost to follow-up. Conversely, in case 2, the 62-year-old female patient underwent systemic chemotherapy, but no surgical treatment, and in case 3, the 51-year-old male patient underwent complete tumor resection and received systemic chemotherapy for late tumor recurrence. Early diagnosis of osteosarcoma in elderly patients is difficult, and misdiagnosis or a missed diagnosis is common. In clinical practice, bone tumors in elderly patients should be investigated carefully. Imaging examinations are essential for diagnosis, and biopsy is required for confirmation. However, the efficacy of chemotherapy for elderly patients with primary osteosarcoma remains uncertain. Collectively, due to the small number of reports of osteosarcoma in the elderly population, the 3 cases in the present study raise awareness of this rare condition. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is the most common bone tumor in children and young adults, and is an aggressive tumor with poor prognosis. MicroRNAs (miRNAs) are aberrantly expressed in various types of cancer, and contribute to cancer tumorigenesis and progression. In the present study, the potential prognostic value and biological function of miRNA-136 (miR-136) in OS was investigated. Reverse transcription-quantitative polymerase chain reaction analysis was used to evaluate the expression of miR-136 in OS tissues and cell lines. Kaplan-Meier survival analysis and Cox regression analysis were conducted to investigate the prognostic significance of miR-136. Various in vitro cell based assays were used to evaluate the effects of miR-136 on the biological behavior of OS cells. A luciferase assay was performed to determine the key miR-136 targets associated with OS. The expression of miR-136 was significantly downregulated in osteosarcoma tissues and cells compared with the normal controls (all P<0.05). Decreased miR-136 expression was significantly associated with Enneking staging (P=0.030) and distant metastasis (P=0.016). Decreased miR-136 expression in patients was associated with shorter overall survival compared with patients with increased expression levels (log-rank test; P<0.05). The expression of miR-136 was indicated as an independent prognostic factor for the patients (hazard ratio=0.496; 95% confidence interval=0.250–0.987; P=0.046). MTT, transwell and Matrigel assays demonstrated that upregulation of miR-136 decreased proliferation, migration and invasion of OS cells. Bioinformatics and luciferase assays demonstrated that migration and invasion enhancer 1 (MIEN1) is a direct target of miR-136. Together, the results suggested that miR-136 functions as a tumor suppressor gene to regulate proliferation, migration and invasion of OS cells. MIEN1 was a potential target of miR-136. Additionally, miR-136 may serve as a prognostic biomarker for OS. [ABSTRACT FROM AUTHOR]

The combination of cetuximab (CTX) and chemotherapy, such as FOLFOX or FOLFIRI, is currently the standard treatment for metastatic colorectal cancer (mCRC). Zoledronic acid (ZOL) is used in patients with bone metastasis. We herein report our experience with the case of a 58-year-old male patient with metastatic rectal cancer who was treated with ZOL + CTX as third-line therapy, and in whom this combination appeared to be effective. Although the patient developed bone metastasis and cardiac tamponade due to the recurrence of rectal cancer, he survived for approximately 10 months after the initiation of ZOL and CTX treatment. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate whether interleukin-8 (IL-8) enhances the ability of prostate cancer bone metastasis by influencing the coding level of bone sialoprotein (BSP). Cultured prostate cancer cell lines LNCaP (androgen dependent) and DU145 (androgen independent) were divided into three groups: IL-8 treatment group; IL-8 receptor inhibitor (SB225002) treatment group; and control group. Western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to detect BSP protein and mRNA expression levels. Matrigel and bone adhesion experiments were used to detect the invasiveness of cancer cells and bone adhesion changes. Compared with the control group, western blotting and RT-qPCR results indicated that BSP protein and mRNA levels in LNCaP and DU145 were significantly upregulated following IL-8 treatment. Matrigel experiments indicated that following IL-8 treatment, the invasiveness of LNCaP and DU145 cells was significantly increased. The results of bone adhesion experiments indicated that following IL-8 treatment, the number of DU145 cells adhered to the surface of the bone was increased, compared with the control group. Following treatment of both cell lines with SB225002, western blotting and RT-qPCR results indicated that the expression levels of BSP protein and mRNA were significantly downregulated. Matrigel experiments indicated that following SB225002 treatment, the invasiveness of LNCaP and DU145 cells was significantly reduced. The number of DU145 cells adhered to the surface of the bone was reduced, compared with the untreated group. Therefore, IL-8 may promote prostate cancer bone metastasis by enhancing BSP regulation. [ABSTRACT FROM AUTHOR]

Clinical value of PET/CT (positron emission tomography/computed tomography) in the diagnosis of malignant bone tumors (BT) was investigated. Fifty-four patients with BT were first diagnosed by ordinary CT and then by PET/CT. The diagnostic efficacy outcomes and diagnosis of malignant BT by clinical stage of the two methods for BT were observed and recorded, and the diagnostic value of PET/CT in the diagnosis of BT was evaluated. There were 14 cases of benign BT patients, 15 cases of stage I, 10 cases of stage II and 15 cases of stage III in malignant BT patients. The diagnostic coincidence rate of PET/CT was 92.59% and the diagnostic coincidence rate of CT was 72.22%, which showed that the diagnostic coincidence rate of PET/CT was significantly higher than that of CT (P<0.05). The sensitivity, negative predictive value and positive predictive value of PET/CT were 95.00, 85.71 and 95.00%, respectively, which were higher than those of CT (P<0.05). CT and PET/CT were used for the clinical staging and pathological diagnosis of malignant BT; the results showed that the diagnostic accuracy of PET/CT in the clinical stages of malignant BT was also significantly higher than that of CT (P<0.05). The diagnostic efficacy of PET/CT in BT is better than that in CT. PET/CT can diagnose the pathological properties of BT more accurately, and can also effectively diagnose the clinical stage of malignant BT and provide clinical diagnostic basis for follow-up procedures. [ABSTRACT FROM AUTHOR]

The aim of the present study was to characterize the morphological parameters of giant cell tumor of bone (GCTB) in the knee. The imaging data of 250 patients with GCTB in the knee were retrospectively reviewed, and the morphological parameters were analyzed. The study included 137 cases with GCTB in the distal femur and 113 cases with GCTB in the proximal tibia. The maximal longitudinal diameter of the tumor was 6.616±2.322 cm in the femur group and 5.738±2.278 cm in the tibia group (P=0.003). The maximal transverse diameter in the two groups was 4.865±1.525 and 4.313±1.309 cm, respectively (P=0.003). The shortest distance from the articular surface (SDAS) in the two groups was 0.381±0.404 and 0.280±0.328 cm, respectively (P=0.035), whereas the longest distance from the articular surface in the two groups was 6.924±2.135 and 5.878±1.825 cm, respectively (P=0.001). There were statistically significant differences between the two groups in terms of the range of SDAS (P=0.043). Additionally, the incidence of pathological fractures in the femur was higher compared with that in the tibia (P=0.001), and the incidence of pathological fractures in the two groups gradually increased with the increase in lesion diameter. GCTB in the distal femur was larger compared with that in the proximal tibia, whereas GCTB in the tibia was closer to the articular surface compared with that in the femur. Furthermore, the incidence of pathological fractures in the femur was higher compared with that in the tibia. [ABSTRACT FROM AUTHOR]

Effective therapies are limited for pancreatic cancer, particularly for those with distant tumour metastases. Therefore, more individualised drug screening is urgently required. Next-generation sequencing (NGS) is a powerful tool to investigate the genomic landscape of patients and the mechanism of drug response, which may provide a broader vision for potential clinical drug screening. Patient-derived xenograft (PDX) models may have a significant advantage in predicting clinical treatment response. In our previous study, a PDX of pancreatic cancer bone metastasis was established, and NGS was conducted to investigate the molecular information. In the present study, these data were further analysed and fibroblast growth factor receptor 1 (FGFR1) amplification was identified in a panel of 416 cancer-associated genes. Thus, AZD4547, an inhibitor against FGFR, was selected as a potential therapy, and was evaluated using the PDX model. AZD4547 was shown to exhibit antitumor activity by reducing the expression of FGFR1 and its targets. The present study also demonstrated the high potential of the novel NGS/PDX-based drug screening platform to improve individualised cancer treatment. [ABSTRACT FROM AUTHOR]

The most frequent site of recurrence in breast cancer (BC) is the bone, particularly in patients with 'luminal-like' disease. Denosumab has been shown to prevent aromatase inhibitors (AIs) induced bone resorption in postmenopausal early BC patients and reduce skeletal-related events (SREs) in bone metastatic breast cancer (BMBC). A 'real life' analysis of 90 BMBC patients treated with denosumab was performed. Eighty-six patients (95.6%) had 'luminal-like' disease, 72 (80%) had bone metastases at the time of first recurrence of disease. Among 50 patients with metachronous 'luminal-like' disease, 40 (80%) had first recurrence to the bone. Among these patients median time to skeletal recurrence (TSkR) was shorter for patients who were previously exposed to AIs compared to those who were not (53.0 vs. 102.0 months, respectively; P=0.0300) and longer for patients previously treated with tamoxifen compared to those who were not (102.0 vs. 59.0 months, respectively; P=0.0466). Both of them were not confirmed at multivariate analysis. In the overall population, 17 first SREs were observed (16 radiation therapy) and median time to first SRE was not reached. A statistically significant difference in the incidence of SREs was detected only between patients with exclusively osteolytic bone metastases vs. those without (P=0.013). The presence of exclusively-osteolytic bone metastases was the only factor significantly associated with a shorter time to first SRE (P=0.011). The only G3 toxicity reported was hypocalcemia in one patient. No osteonecrosis of the jaw events (ONJ) occurred. This study demonstrated that a pro-active attitude enables the treatment of the majority of patients with denosumab without significant class-related toxicities. The majority of SREs were from radiation therapy, so pain still remains the clinical hallmark of bone metastases, particularly for osteolytic ones. The suggestion that estrogen deprivation with AIs can favor a 'bone-related' risk conditions for developing bone metastases must be considered with caution and surely needs further validations. [ABSTRACT FROM AUTHOR]

Bone cancer is one of the most common tumor types that occurs in bones and their affiliated tissues. The prognosis remains poor due to the limited number of effective therapeutic targets. Downregulation of bone morphogenetic protein and activin membrane‑bound inhibitor (BAMBI) has been observed in human cancer cells and BAMBI reconstitution can inhibit growth and metastasis of human cancer cells. In the present study, a potential mechanism mediated by BAMBI in osteosarcoma cells was investigated. The data demonstrated that BAMBI reconstitution suppressed the cell growth, migration and invasion of the osteosarcoma cell lines SAOS2 and MG63. Alterations to the epithelial‑to‑mesenchymal transition (EMT) marker expression were observed in BAMBI‑treated osteosarcoma SAOS2 and MG63 cells. The apoptosis rate of SAOS2 and MG63 cells induced by cisplatin were increased in BAMBI‑treated osteosarcoma SAOS2 and MG63 cells via downregulation of the anti‑apoptosis genes P16, P21 and B‑cell lymphoma 2. The potential mechanism investigated indicated that BAMBI administration downregulated the transforming growth factor‑β (TGF‑β) signaling pathway, whilst knockdown of BAMBI upregulated the TGF‑β signaling pathway in SAOS2 and MG63 cells. Reconstitution of BAMBI in SAOS2 and MG63 cells resulted in a notable reduction of TGF‑β‑induced EMT, cell growth, migration and invasion in vitro. In conclusion, the results demonstrated that BAMBI reconstitution inhibited growth and invasiveness of osteosarcoma, as well as promoted the apoptotic sensibility, which indicated that the TGF‑β‑induced EMT signaling pathway may be regarded as a potential target for osteosarcoma therapy. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to investigate the anticancer effects of β-elemene and paclitaxel for bone neoplasms. MTT assay, reverse transcription-quantitative polymerase chain reaction, western blotting, flow cytometry and immunostaining were used to analyze the combined effects of β-elemene and paclitaxel both in vitro and in vivo. The results demonstrated that combined treatment of β-elemene and paclitaxel (β-elemene-paclitaxel) significantly inhibited growth and aggressiveness of U-2OS cells compared with either β-elemene or paclitaxel treatment alone. It was demonstrated that β-elemene promoted paclitaxel-induced apoptosis of U-2OS cells. Anti-apoptosis B-cell lymphoma (Bcl)-2 and Bcl-w genes were downregulated and pro-apoptotic Bcl-2-associated agonist of cell death and caspase-3 genes were upregulated in U-2OS cells following treatment with β-elemene-paclitaxel. Treatment of β-elemene-paclitaxel arrested the cell cycle and decreased cyclin-dependent kinase, cyclin-B1, P21 and P27 expression levels and decreased resistant genes alterations of ATP binding cassette subfamily B member 1, LDL receptor related protein and TS in U-2OS cells. Results demonstrated that β-elemene-paclitaxel decreased G-protein coupled receptor 124 (GPR124), vascular endothelial growth factor receptor, matrix metallopeptidase (MMP)-3, MMP-9 expression levels and increased endostatin, TIMP metallopeptidase inhibitor (TIMP)-1, TIMP-2 expression in U-2OS cells. In vivo assay demonstrated that β-elemene-paclitaxel treatment inhibited tumor growth of BALB/c-nu/nu nude mice and prolonged survival rate of tumor-bearing mice. Immunostaining demonstrated that β-elemene-paclitaxel treatment increased apoptotic bodies, GPR124 and increased endostatin, TIMP-1 and TIMP-2 expression in tumor tissues. In conclusion, these results suggest that the combined treatment of β-elemene-paclitaxel is more effective at inhibiting bone neoplasm growth than β-elemene or paclitaxel single treatment GPR124. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS), a common and primary malignant bone tumor, is characterized by highly aggressive potency. Baicalein, a bioactive flavone isolated from Scutellaria baicalensis Georgi, has been shown to inhibit the progression of numerous tumors, including OS. However, the mechanisms by which baicalein protects against OS are still largely unknown. The results of the present study showed that administration of baicalein significantly inhibited the proliferation, migration and invasion and promoted apoptosis in MG-63 and Saos-2 cells. Ezrin was identified as a target gene of microRNA (miR)-183. MG-63 and Saos-2 cells treated with baicalein exhibited increased miR-183 levels and decreased Ezrin expression. Importantly, miR-183 inhibition and Ezrin overexpression abolished the effects of baicalein on MG-63 and Saos-2 cell proliferation, migration, invasion and apoptosis. Taken together, these findings suggest that baicalein inhibits the proliferation, migration and invasion and induces apoptosis in OS cells by activating the miR-183/Ezrin pathway, revealing a novel mechanism underlying anti-OS effects of baicalein. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most common malignant bone carcinoma that primarily occurs between childhood to adolescence. It was suggested by recent research that the Brain type glycogen phosphorylase (PYGB) gene may serve an important role in various types of cancer. In the present study, the PYGB gene was knocked down in order to evaluate the cell viability, invasion and migration of the human osteosarcoma cell lines MG63 and HOS. The expression levels of PYGB in osteosarcoma and bone cyst tissue samples, as well as in the osteosarcoma cell lines were identified using reverse transcription-quantitative polymerase chain reaction and western blot assay. Subsequently, a Cell Counting kit 8 assay was employed to evaluate cell proliferation. Cell apoptosis rate and cell cycle distribution were measured by flow cytometry. In addition, cell invasion and migration were evaluated through a Transwell assay. The expression levels of the cell apoptosis and tumor metastasis associated proteins B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein, E-cadherin, Twist, matrix metalloproteinase (MMP)-9 and MMP2 were measured via western blotting. PYGB exhibited a higher expression level in the osteosarcoma tissue samples, particularly in the human osteosarcoma cell lines MG63 and HOS. Knockdown of PYGB resulted in a decline in cell proliferation, invasion and migration, which was coupled with induced cell apoptosis and cell cycle arrest in MG63 and HOS cells. Furthermore, alterations in the expression of apoptosis and metastasis associated proteins indicated that small interfering (si)PYGB may have regulated cell viability by targeting the Bcl/Caspase and cyclin dependent kinase (CDK)-1 signaling pathway. In conclusion, PYGB siRNA exerted an inhibitory effect on the cell viability of the human osteosarcoma cells MG63 and HOS by blocking the Caspase/Bcl and CDK1 signaling pathway, highlighting novel potential therapeutic methods for treating osteosarcoma. [ABSTRACT FROM AUTHOR]

Osteosarcoma is a common type of human carcinoma, which exhibits a high metastasis and recurrence rate. Previous studies have indicated that long non-coding RNA phosphatase and tensin homolog pseudogene 1 (lnPTENP1) has tumor suppressive action by modulating PTEN expression in different types of tumor cells. However, the potential mechanism by which lnPTENP1 has an effect in osteosarcoma cells remains elusive. In the present study, the role of lnPTENP1 in osteosarcoma cells was investigated and the possible mechanisms by which it functions were explored. It was revealed that lnPTENP1 transfection significantly inhibited osteosarcoma cell growth, proliferation, migration and invasion. LnPTENP1 transfection also significantly promoted apoptosis in Mg63 cells treated with tunicamycin. Further analysis revealed that lnPTENP1 transfection regulated osteosarcoma cell growth via the PI3K/AKT signaling pathway. In vivo assays revealed that lnPTENP1 transfection significantly inhibited osteosarcoma tumor growth and significantly increased the protein expression and phosphorylation levels of PI3K and AKT. In conclusion, the results of the present study indicated that lnPTENP1 may inhibit osteosarcoma cell growth via the PI3K/AKT signaling pathway, which may be a potential novel target for human osteosarcoma therapy. [ABSTRACT FROM AUTHOR]

The seven-amino acid truncated (7ND) protein is an N-terminal deletion mutant of monocyte chemoattractant protein-1 (MCP-1) and it functions as a dominant-negative inhibitor. 7ND and wild-type MCP-1 form a heterodimer, which binds to MCP-1 receptors and inhibits monocyte chemotaxis. In the present study, the 7ND protein was cloned, expressed and purified. An MTT assay revealed that the proliferation of oral squamous cell carcinoma (OSCC) SCC25 cells was not affected following 3 days of treatment with synthetic 7ND protein. Serial dilutions of the 7ND protein were tested for monocyte migration and osteoclast differentiation, and tartrate-resistant acid phosphatase staining demonstrated that significantly fewer osteoclasts were differentiated from cluster of differentiation 14+ (CD14+) monocytes using magnetic activated cell sorting. Immunofluorescence confirmed these results and significantly less F-actin staining was observed in 7ND-treated osteoclasts. Furthermore, bone invasion was examined by subcutaneously injecting SCC25 cells into the area overlaying the calvariae of nude mice. The results demonstrated that the average tumor volume of SCC25 cells with 7ND protein was similar to the average volume of tumors formed by untreated SCC25 cells. Flow cytometric analysis suggested that the CD14+ subpopulation in the bone marrow of 7ND-treated mice was reduced compared with that of untreated mice. Micro-computed tomography imaging revealed significantly less bone resorption in the calvariae injected with SCC25 cells plus the 7ND protein. Taken together, the results of the present study demonstrated the potential therapeutic value of the 7ND protein. The 7ND MCP-1 variant not only functions in vitro to inhibit osteoclast differentiation, but also reduces the progression of bone invasion by OSCC cells in vivo. [ABSTRACT FROM AUTHOR]

Non-Hodgkin lymphoma of the bone is rare and typically causes an extensive bone lesion. The present study describes a case of diffuse large B-cell primary non-Hodgkin lymphoma of the bone, which occurred in the right femur, and was initially treated with surgery and chemotherapy. Following a 7-year period of complete remission, a new, similar lesion was identified in the left femur. With both lesions, there was no accompanying destruction of any other bones or organ involvement. Metastasis of PLB to the contralateral side is extremely rare and, to the best of our knowledge, this is the first report of this particular presentation in China or worldwide. We hypothesized that the present situation arose due to mechanisms involving the tumor microenvironment, circulating tumor cells, lymphocyte homing and self-seeding. The present report describes the case in detail, and discusses the possible underlying mechanisms and their potential contribution to the treatment of non-Hodgkin lymphoma, as well as the prevention of metastasis and recurrence, which may be of considerable clinical significance. [ABSTRACT FROM AUTHOR]

Ewing's sarcoma (EWS) is a highly aggressive bone cancer that affects children and adolescents. Despite advances in multimodal management, 5-year event-free survival rates for patients presenting with metastases at diagnosis remain at 25%. As key regulators of actin organization, the Rho-associated coiled-coil containing protein kinases, ROCK1 and ROCK2, have been associated with cancer dissemination and poorer prognosis. Recently, in vitro data indicating ROCK2 as a molecular target for the treatment of EWS has been presented. Nonetheless, a deeper exploration of the contribution of this kinase dysregulation in EWS is still necessary. In this regard, the present study aimed to evaluate the expression of ROCK1 and ROCK2 in 23 pediatric tumor samples and to verify the prospect of using their pharmacological inhibition through functional assays. Our results showed positive immunostaining for ROCK1 and ROCK2 in the majority samples (75 and 65%, respectively). A significantly increased risk of incomplete remission in patients with positive immunostaining for ROCK2 was found (P=0.026), though no correlations with other prognostic features (huvos classification, FLI1/EWS status, relapse, metastasis or death) were observed. Associations with survival were merely suggestive. Apparent protein expression of both kinases was also found in EWS cell lines (SK-ES-1 and RD-ES). Treatments with selective ROCK inhibitors did not alter cell viability or migration in vitro. However, a significant increase in invasion was observed after treatment with SR3677 (ROCK2 inhibitor) and hydroxyfasudil (pan-inhibitor). Consequently, even though the majority of EWS samples included in our study showed positivity for ROCK1 and ROCK2, the lack of significant associations with prognosis and absence of appropriate responses to their inhibition in vitro does not support their prospective use as therapeutic targets for the treatment of this metastatic tumor. Larger cohort studies might provide more evidence on whether there is a specific role of ROCK kinases in EWS physiopathology. [ABSTRACT FROM AUTHOR]

Naked cuticle homolog 1 (NKD1), a negative modulator of the canonical Wnt/β-catenin pathway, is expressed in multiple normal tissues. However, there is little information regarding NKD1 expression in osteosarcoma. The aim of the present study was to explore the expression and clinicopathological significance of NKD1 in human osteosarcoma. In the present study, NKD1 protein and mRNA expression levels were detected by western blotting and reverse transcription-quantitative polymerase chain reaction, respectively. The results revealed that NKD1 expression levels were significantly lower in osteosarcoma tissues compared with normal bone tissue, and were significantly lower in patients with lung metastasis compared with patients without lung metastasis. In addition, with increasing Enneking stage, the NKD1 expression levels decreased. These data indicated that reduction of NKD1 may be associated with carcinogenesis, lung metastasis and Enneking stage in osteosarcoma. This interpretation is consistent with the results obtained from experiments on MG63 osteosarcoma cells in vitro. In order to explore the function of NKD1 in osteosarcoma, the expression of NKD1 in the human osteosarcoma MG-63 cell line was upregulated by transfection with an adenovirus containing an NKD1 vector. The results revealed that upregulation of NKD1 expression reduced the proliferation and migration of osteosarcoma cells by inhibiting expression of β-catenin, cyclin D1 and MMP-9 protein. These data suggested that the downregulation of NKD1 may be involved in the proliferation and migration of osteosarcoma cells through the activation of the canonical Wnt signaling pathway, and it may be a potential prognostic marker and therapeutic target for patients with osteosarcoma. [ABSTRACT FROM AUTHOR]

Osteosarcoma remains the most prevalent primary malignant bone tumor in children and young adults globally. Therefore, novel and highly effective antitumor agents are urgently required. Elemene is a natural plant compound extracted from the medicinal Chinese herb, Rhizomazedoariae, which has been employed as an antitumor agent for the treatment of a number of tumors, including osteosarcoma. However, the mechanisms underlying its antitumor effect are currently unclear. The human osteosarcoma cell lines, MG.63 and U2OS, were employed in the present study. MTT, migration, transwell invasion and terminal deoxynucleotidyltransferase.mediated deoxy.UTP.fluorescein nick end.labeling assays were performed to evaluate cell viability, migration, invasion and apoptosis, respectively. Western blotting and immunohistochemistry analyses were performed to measure the levels of renin.angiotensin system (RAS) components. In order to evaluate the effect of elemene on tumor weight and volume, MG.63 and U2OS cells were injected into mice. Treatment of osteosarcoma cell lines, MG.63 and U2OS, with elemene led to the inhibition of cell viability, migration and invasion, as well as induction of cell apoptosis. In addition, elemene treatment downregulated the expression of a number of RAS components. The growth of osteosarcoma cell.transplanted tumors in nude mice and angiotensin II expression were inhibited by elemene treatment. The results of the present study indicate that the antitumor effects of elemene may partly be due to downregulation of the RAS signaling pathway, and that RAS may be a putative pharmacological target for osteosarcoma therapy. [ABSTRACT FROM AUTHOR]

Bone cancer is one of the most lethal malignancies and the specific causes of tumor initiation are not well understood. B-cell-specific Moloney murine leukemia virus integration site 1 protein (Bmi-1) has been reported to be associated with the initiation and progression of osteosarcoma, and as a prognostic indicator in the clinic. In the current study, a full-length antibody targeting Bmi-1 (AbBmi-1) was produced and the preclinical value of Bmi-1-targeted therapy was evaluated in bone carcinoma cells and tumor xenograft mice. The results indicated that the Bmi-1 expression level was markedly upregulated in bone cancer cell lines, and inhibition of Bmi-1 by AbBmi-1 reduced the invasiveness and migration of osteosarcoma cells. Overexpression of Bmi-1 promoted proliferation and angiogenesis, and increased apoptosis resistance induced by cisplatin via the nuclear factor-κB (NF-κB) signal pathway. In addition, AbBmi-1 treatment inhibited the tumorigenicity of osteosarcoma cells in vivo. Furthermore, AbBmi-1 blocked NF-κB signaling and reduced MMP-9 expression. Furthermore, Bmi-1 promoted osteosarcoma tumor growth, whereas AbBmi-1 significantly inhibited osteosarcoma tumor growth in vitro and in vivo. Notably, AbBmi-1 decreased the percentages of Ki67-positive cells and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells in tumors compared with Bmi-1-treated and PBS controls. Notably, MMP-9 and NF-κB expression were downregulated by treatment with AbBmi-1 in MG-63 osteosarcoma cells. In conclusion, the data provides evidence that AbBmi-1 inhibited the progression of osteosarcoma, suggesting that AbBmi-1 may be a novel anti-cancer agent through the inhibition of Bmi-1 via activating the NF-κB pathway in osteosarcoma. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is the most common primary bone cancer, and frequently leads to mortality as a result of rapid proliferation and metastasis. Recent data highlight the important role of microRNAs (miRs) in human cancers, including OS, providing a novel method for its diagnosis and treatment. In the present study, it was identified that miR‑491‑3p expression was frequently decreased in OS tissues and OS cell lines. Restored miR‑491‑3p expression suppressed the growth and invasion of OS cells. Bioinformatics and experimental analysis indicated that tetraspanin 1 (TSPAN1) is a direct target of miR‑491‑3p in OS. The TSPAN1 mRNA level was inversely associated with the miR‑491‑3p level in OS tissues and cell lines. Consistent with this, TSPAN1 knockdown inhibited the growth and invasion of OS cells. In conclusion, these data provide compelling evidence that miR‑491‑3p functions as a tumor suppressor in OS to attenuate the potential of growth and invasion by targeting TSPAN1. [ABSTRACT FROM AUTHOR]

Osteosarcoma is among the most malignant types of tumor worldwide and has become a leading contributor to tumor incidence, particularly in adolescents. Resistance to conventional treatment and the complexity of osteosarcoma tumorigenesis has resulted in high mortality rates. MicroRNAs are a class of noncoding RNAs, which regulate numerous biological processes. However, the involvement of miR‑643 in osteosarcoma remains to be elucidated. In the present study, reverse transcription‑quantitative polymerase chain reaction, luciferase reporter assay, invasion assay, viability assay, western blot analysis and in vivo implantation were performed to analyze the action of miR‑643 in osteosarcoma. The results demonstrated that miR‑643 inhibited the progression of osteosarcoma and acted as a potential tumor suppressor. The expression of miR‑643 was downregulated in osteosarcoma tissues and cell lines. In addition, miR‑643 transfection significantly impaired the proliferation and invasion of osteosarcoma cells. The present study also identified Zinc finger E‑box‑binding homeobox 1 (ZEB1) as a direct target of miR‑643, and the ectopic expression of ZEB1 counteracted the effect of miR‑643 transfection. A significant inverse correlation was also found between the expression of miR‑643 and ZEB1. A low expression of miR‑643 or a high expression of ZEB1 was associated with poor patient survival rates. The results of the present study suggested that the decreased expression of miR‑643 may be involved in the mechanism underlying the development of osteosarcoma. The intricate interactions between miR‑643 and ZEB1 may serve as a potential therapeutic target in osteosarcoma oncogenesis. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is among the most common primary tumors of bone tissue, and occurs primarily in children and young adults. Despite the development of novel therapeutic approaches, the prognosis of OS remains poor. MicroRNAs (miRNAs) are involved in the development and progression of various types of human cancer and may have potential as novel therapeutic targets for cancer treatment. The present study aimed to investigate the expression and biological functions of miRNA‑25‑3p in OS, and explore the molecular mechanisms underlying its actions. In the present study, miRNA‑25‑3p was detected in OS tissues and cell lines. The functional roles of miRNA‑25‑3p in OS cells were evaluated using a Cell Counting Kit 8 assay and cellular migration and invasion assays. The molecular mechanisms underlying the tumor‑suppressing roles of miRNA‑25‑3p in OS were explored using bioinformatics analysis, luciferase reporter assay, western blotting and the reverse transcription‑quantitative polymerase chain reaction. The expression of miRNA‑25‑3p was revealed to be downregulated in OS tissues and cell lines compared with non‑tumor bone tissues and normal osteoblasts, respectively. miRNA‑25‑3p overexpression was demonstrated to significantly suppress the proliferation, migration and invasion of OS cells in vitro. In addition, sex‑determining region‑related high mobility group box (SOX) 4 was identified as a direct target gene of miRNA‑25‑3p, and was further investigated. Similarly to miRNA‑25‑3p overexpression, SOX4 knockdown was demonstrated to suppress OS cell proliferation, migration and invasion. Furthermore, SOX4 expression was revealed to be significantly upregulated in OS tissues compared with in adjacent non‑tumor bone tissues, and Spearman's correlation analysis indicated a negative correlation between SOX4 mRNA and miRNA‑25‑3p expression levels in OS tissues. The present findings suggested that miRNA‑25‑3p may act as a tumor suppressor by targeting SOX4 expression in bone tissue. Therefore, miRNA‑25‑3p may have potential as a novel therapeutic target for the treatment of patients with OS. [ABSTRACT FROM AUTHOR]

Recent evidence has suggested that microRNAs (miRs), which are a class of non‑coding RNAs, serve diverse roles in tumorigenesis. However, the role of miR‑635 in osteosarcoma (OS) remains unknown. The present study revealed that miR‑635 may be a tumor suppressive miR. The expression of miR‑635 was significantly decreased in OS specimens. In addition, the proliferation and invasion of OS cells transfected with miR‑635 may be effectively attenuated. Transfection of cells with miR‑635 may further inhibit tumor growth in vivo. miR‑635 may antagonize tumorigenesis of OS possibly by inducing apoptosis, as demonstrated by flow cytometric analysis and caspase‑3 kinase assays. The data of the present study suggested that miR‑635 may be a novel tumor suppressor and may serve as a putative diagnostic marker for patients with OS. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most common primary malignant bone cancer in children and adolescents. Unfortunately, treatment failures are common due to metastasis and chemore­sistance, however, the underlying molecular mechanism remains unclear. Accumulating evidence indicated that the homeobox B7 (HOXB7) gene was associated with the development of cancer. However, the expression and function of HOXB7 in osteosarcoma is still unknown. In the current study, the expression of HOXB7 was upregulated in osteosarcoma tissues and cells compared with paired adjacent non‑tumor bone tissues and osteoblastic cells using reverse transcription‑quantitative polymer chain reaction and western blotting. HOXB7 knockdown dramatically suppressed cell viability, proliferation, migration and epithelial‑mesenchymal transition. Moreover, downregulation of HOXB7 expression significantly inhibited matrix metalloproteinase (MMP)2 and MMP7 protein levels in the MG63 cell line. Therefore, the present results identified that HOXB7 could play a critical role in carcinogenesis, and may serve as a therapeutic target for the treatment of osteosarcoma. [ABSTRACT FROM AUTHOR]

Surgery followed by radiotherapy is the standard treatment for chordomas, which are a rare but low-grade type of bone cancer arising from remnants of the embryonic notochord. However, disease recurrence following radiotherapy is common, most likely due to endogenous DNA repair mechanisms that promote cell survival upon radiation strikes. The ataxia telangiectasia mutated/ataxia telangiectasia mutated and Rad3 related (ATM/ATR)-mediated pathway has a critical role in DNA repair mechanisms; however, it has rarely been investigated in chordomas. In the present study, the expression of signal molecules related to the ATM/ATR pathway in chordoma tissues and adjacent normal tissues were initially examined using immunohistochemistry and western blot analysis. Chordoma U-CH1 and U-CH2 cells were subsequently used to investigate cell responses to ionizing radiation and the potential protective actions mediated by the ATM/ATR pathway. Phosphorylated (p)-ATM, p-ATR, γ-H2A histone family, member X (H2AX) and RAD51 were significantly upregulated in chordoma tissues relative to adjacent normal tissues (P<0.05). No significant reductions were observed in the viability of U-CH1 and U-CH2 cells following exposure to low-dose (1 and 2 Gy) radiation. Radiation (1 and 2 Gy) triggered a significant upregulation in p-ATM, γ-H2AX and RAD51 expression in U-CH1 cells (P<0.05), as well as a significant upregulation in p-ATM, p-ATR and RAD51 levels in U-CH2 cells (P<0.05). RAD51 knockdown increased the responses of both U-CH1 and U-CH2 cells to 1 Gy radiation, as evidenced by the significantly decreased cell viability and increased apoptosis rate (P<0.05). Collectively, the results of the present study indicated that radioresistance of chordoma cells is associated with the ATM/ATR pathway, in which RAD51 serves as an important downstream effector. Thus, RAD51 presents a promising therapeutic target for improving the outcome of radiotherapy treatment in chordomas. [ABSTRACT FROM AUTHOR]

Osteoblastomas are benign bone tumors that produce prostaglandin and promote inflammation. The aim of the present study was to describe the clinical and radiological characteristics of a pediatric osteoblastoma case over an 8-month postoperative follow-up. The case involved an 11-year-old female patient with normal somatic development, presenting with a chief complaint of sleep disturbance. The patient had no spontaneous pain or other readily evident possible causes. Magnetic resonance imaging (MRI) revealed a neoplastic lesion in the sacrum, with peritumoral edema. Intraoperative fast-frozen biopsy raised the suspicion of osteosarcoma. However, the final diagnosis was osteoblastoma and a second operation was performed for total resection. The edematous peritumoral bone and muscle tissues were preserved. Following total removal of the tumor, the sleep disturbance resolved. Eight months after the surgery, MRI revealed no recurrence of the tumor and reduction of the peritumoral edema. On immunohistochemical examination, cyclooxygenase (COX)-1 and COX-2 were strongly positive, indicating that the tumor activated the arachidonic acid metabolic pathway and produced prostaglandin. The inflammatory process subsequently promoted the development of peritumoral edema and induced the sleep disturbance. [ABSTRACT FROM AUTHOR]

Bone cancer pain commonly occurs when tumors originating in the breast, prostate or lung metastasize to long bones, spinal vertebrae and/or the pelvis. However, the underlying mechanisms of bone cancer pain remain largely unknown. The present study aimed to determine the role of spinal tumor necrosis factor-α (TNF-α) in the development of bone cancer pain. Osteosarcoma NCTC 2472 cells were implanted into the femoral intramedullary space of C3H/HeJ mice to establish a bone cancer model. Resulting pain-related behaviors, namely spontaneous foot lifting, paw withdrawal mechanical threshold and paw withdrawal thermal latency were observed prior to inoculation and on days 3, 5, 7, 10 and 14 thereafter. Reverse transcription-quantitative polymerase chain reaction was also performed to assess the levels of TNF-α mRNA within the spinal cord. In addition, the effects of the TNF-α antagonist etanercept on TNF-α levels and pain behaviors were evaluated. It was observed that the levels of TNF-α mRNA in the spinal cord were significantly higher in tumor-bearing mice 10 days post-inoculation, which was accompanied by increases in spontaneous flinching, mechanical hyperalgesia and thermal hyperalgesia, relative to control mice. Etanercept attenuated the bone cancer-induced increase in TNF-α and pain-related behaviors. These results suggest that etanercept may be a potential therapeutic for the treatment of bone cancer pain. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that fatty acid synthase (FASN) is overexpressed in osteosarcoma (OS) cells and tissues and, therefore, knockdown of FASN may inhibit OS cell proliferation, migration and invasion via regulation of the human epidermal growth factor receptor 2 (HER2)/phosphoinositide 3-kinase (PI3K)/protein kinase B(Akt) signaling pathway in vitro. However, the tumor microenvironment has a crucial role in the determination of tumor malignant phenotype. The aim of the present study was to investigate the effect of knockdown of FASN on OS progression and the potential molecular mechanism in nude mice with orthotopic tumor implants in vivo. Results demonstrated that the knockdown of FASN markedly suppressed the growth and metastasis of OS, at least partially, by blocking the HER2/PI3K/Akt signal pathway in mice with intratibial 143B OS xenografts. These results suggest that the FASN/HER2/PI3K/Akt signaling pathway may be a potential therapeutic target for OS management. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the significance of the phosphorylation of mitogen-activated protein kinase (MAPK) and the protein expression of cyclin D1 in human osteosarcoma tissues. Human osteosarcoma tissue samples were collected from 30 patients, benign bone tumor samples were collected from 30 patients, and normal bone tissues were collected from 10 individuals as controls. Immunohistochemistry was performed to measure the levels of phosphorylated (p)-MAPK and cyclin D1 protein in cases of human osteosarcoma. The results showed that the positive rates of MAPK and cyclin D1 in osteosarcoma were 86.67% (26/30) and 73.00% (22/30), respectively. The positive staining rates of MAPK and cyclin D1 in benign bone tumor tissues were 10.00% (3/30) and 3.30% (1/30), respectively. The positive rate in the normal bone tissues was 0% (0/30), which was significantly lower, compared with that of the cancerous bone tissue. The positive rates of MAPK and cyclin D1 in osteosarcoma were increased (P<0.05), and the expression of cyclin D1 and p-MAPK were positively correlated. The phosphorylation of MAPK may be important in the development of osteosarcoma, and the overactivation of MAPK may induce high expression of cyclin D1 and induce tumor cells to proliferate continuously. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the possible pathogenesis of osteosarcoma using bioinformatics analysis to examine gene-gene interactions. A total of three datasets associated with osteosarcoma were downloaded from the Gene Expression Omnibus. The differentially expressed genes (DEGs) were identified using the significance analysis of microarrays method, which then were subjected to the Human Protein Reference Database to identify the protein-protein interaction (PPI) pairs and to construct a PPI network of the DEGs. Subsequent multilevel community analysis was applied to mine the modules in the network, followed by screening of the differential expression module using the GlobalAncova package. The genes in the differential expression modules were verified in the valid datasets. The verified genes underwent functional and pathway enrichment analysis. A total of 616 DEGs were selected to construct the PPI network, which included 5,808 osteosarcoma-specific interaction pairs and 8,012 normal-specific pairs. Tumor protein p53 (TP53), mitogen-activated protein kinase 1 (MAPK1) and estrogen receptor 1 (ESR1) were identified the most important osteosarcoma-associated genes, with the highest levels of topological properties. Neurogenic locus notch homolog protein 3 (NOTCH3) and caspase 1 (CASP1) were identified as the osteosarcoma-specific interaction pairs. Among all 23 mined modules, three were identified as differential expression modules, which were verified in the other two datasets. The genes in these modules were predominantly enriched in the FGFR, MAPK and Notch signaling pathways. Therefore, TP53, MAPK1, ESR1, NOTCH3 and CASP1 may be important in the development of osteosarcoma, and provides valuable clues to investigate the pathogenesis of osteosarcoma using the three differential expression modules. [ABSTRACT FROM AUTHOR]

MicroRNA-34 (miR-34), in particular miR-34a, has a negative regulatory effect on osteosarcoma cell proliferation, migration and invasion. Notably, it is also a post-transcriptional regulatory factor of (sex determining region Y)-box 2 (Sox-2), which is required for osteosarcoma cell self-renewal and tumorigenesis. As a direct regulator of Sox-2, miR-34a has been hypothesized to be greatly associated with the regulation of malignancies in osteosarcoma. To investigate the role of miR-34a in the malignancies of osteosarcoma, reverse transcription-quantitative polymerase chain reaction was performed to detect the expression level of miR-34a in osteospheres. The results revealed that the miR-34a, b and c were suppressed in osteosarcoma stem-like cells (OSCs) and osteospheres. The introduction of miR-34a mimics and short hairpin (sh)RNA targeting Sox-2 mRNA (shSox-2) in human OSCs markedly reduced their transformation properties in vitro and their capacity to form tumors in soft agar. Furthermore, the epigenetic expression of miR-34a and shSox-2 inhibited the expression of the stem cell marker, stem cell antigen-1 and led to the failure of osteosphere formation, respectively. The data of the present study indicated that the inhibitory role of miR-34a on tumor growth and metastasis of osteosarcoma may function by reducing the maintenance of osteosphere self-renewal capacity, elimination of tumorigenic ability and invasion of osteosarcoma in vitro. These findings may provide the basis for a novel therapeutic target of osteosarcomas based on inducing the expression of miR-34a. [ABSTRACT FROM AUTHOR]