Osteosarcoma (OS) is the most common primary malignant bone tumor that more commonly occurs in children and adolescents. The most commonly used treatment for OS is surgery combined with chemotherapy, but the treatment outcomes are typically unsatisfactory. High rates of metastasis and post-treatment recurrence rates are major challenges in the treatment of OS. This underlines the need for studying the in-depth characterization of the pathogenetic mechanisms of OS and development of more effective therapeutic modalities. Previous studies have demonstrated the important role of the bone microenvironment and the regulation of signaling pathways in the occurrence and development of OS. In this review, we discussed the available evidence pertaining to the mechanisms of OS development and identified therapeutic targets for OS. We also summarized the available treatment modalities for OS and identified future priorities for therapeutics research.
Child ; Adolescent ; Humans ; Bone Neoplasms/drug therapy* ; Signal Transduction ; Bone and Bones/metabolism* ; Treatment Outcome ; Osteosarcoma/drug therapy* ; Tumor Microenvironment

Chemical investigation of the culture extract of an endophytic Penicillium citrinum from Dendrobium officinale, afforded nine citrinin derivatives (1-9) and one peptide-polyketide hybrid GKK1032B (10). The structures of these compounds were determined by spectroscopic methods. The absolute configurations of 1 and 2 were determined for the first time by calculation of electronic circular dichroism (ECD) data. Among them, GKK1032B (10) showed significant cytotoxicity against human osteosarcoma cell line MG63 with an IC₅₀ value of 3.49 μmol·L^-1, and a primary mechanistic study revealed that it induced the apoptosis of MG63 cellsvia caspase pathway activation.
Apoptosis ; Bone Neoplasms ; Caspases ; Humans ; Osteosarcoma/drug therapy* ; Penicillium

Apoptosis ; Bone Neoplasms/drug therapy* ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Humans ; Matrix Metalloproteinase 2 ; Osteosarcoma ; Ropivacaine/pharmacology*

Osteosarcoma is the most common malignant tumors of bone. Since 1970s, researchers had used chemotherapy drugs to treat osteosarcoma. However, multidrug resistance is a major adverse reaction that affects the efficacy of chemotherapy drugs, leading to the reduced survival rate of osteosarcoma patients. The Notch signaling pathway plays an important role in osteosarcoma proliferation, which affects tumor resistance by reducing intracellular drug accumulation, regulating epithelial-mesenchymal transition, dysregulating microRNA, disrupting the expression of apoptosis genes, and regulating tumor stem cells.
Bone Neoplasms/drug therapy* ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Osteosarcoma/drug therapy* ; Pharmaceutical Preparations ; Receptors, Notch/genetics* ; Signal Transduction

OBJECTIVE: To summarize and critically assess the inhibitory effects of Chinese herbal medicine (CHM) on tumor volume and tumor weight for the treatment of osteosarcoma (OS) in mouse models. METHODS: PubMed, Embase, Web of Science, China Knowledge Resource Integrated Database (CNKI), Wanfang Database, VIP Database, and Chinese BioMedical (CBM) were searched since their inception dates to March 10, 2016. Two reviewers independently selected the controlled studies estimating effects of CHM on mouse OS by administration in vivo. A pair-wise meta-analysis was performed. Twenty-five studies with adequate randomization were included in the systematic review. RESULTS: CHM may significantly inhibit OS growth in mice, as assessed using the tumor weight [20 studies, n=443; 290 for CHM and 153 for the control: pooled mean difference (MD)=-2.90; 95% confidence interval (Cl): -3.50 to -2.31: P<0.01], tumor volume (16 studies, n=382; 257 for CHM and 125 for the control; pooled MD =-2.57; 95% Cl: -3.33 to -1.80; P<0.01) and tumor growth inhibition rate. CONCLUSION CHM could significantly inhibit the growth of OS in mouse models, which might be supportive for the design of preclinical and clinical trials in future.
Animals ; Drugs, Chinese Herbal ; therapeutic use ; Mice ; Osteosarcoma ; drug therapy ; Publication Bias ; Risk Factors ; Tumor Burden ; drug effects ; Xenograft Model Antitumor Assays

PURPOSE: We aimed to determine the prognostic significance of lymphocyte counts and the lymphocytemonocyte ratio (LMR) in pediatric patients with osteosarcoma. METHODS: We retrospectively reviewed the medical records of 27 pediatric patients with localized extremity osteosarcoma, treated at the Korea Cancer Center Hospital between May 2002 and March 2016. Leukocyte counts and LMR before treatment and on day 14 (LMR14) of the first cisplatin-doxorubicin chemotherapy round were evaluated. Patients were dichotomized according to the median value of these parameters, and survival rates were compared. RESULTS: The median age of the 27 patients was 9.9 years (range, 3.2–14.1 years) and tumor sites were: distal femur (n=14), proximal humerus (n=7), proximal tibia (n=2), proximal fibula (n=2), and elsewhere (n=2). Patients were followed up on for a median of 76.4 months (range, 4.5–174.7 months), and 5-year overall (OS) and event-free survival (EFS) rates were 66.0%±9.8% and 60.9%±9.7%, respectively. Patients with a higher pretreatment lymphocyte count (≥2,320/μL) had better OS (90.9% vs. 46.2%, P=0.04) and EFS (83.9% vs. 38.5%, P=0.02). However, the day 14 lymphocyte count was not associated with survival. While no survival difference was observed between patients grouped according to pretreatment LMR (median value, 6.3), patients with a higher LMR14 (≥5) fared better than those with lower LMR14 (5-year OS: 83.3% vs. 46.3%, P=0.04). CONCLUSION: Pretreatment lymphocyte count and LMR during chemotherapy had prognostic significance in pediatric osteosarcoma patients. Further studies involving larger cohorts are necessary to validate our findings.
Cohort Studies ; Disease-Free Survival ; Drug Therapy ; Extremities ; Femur ; Fibula ; Humans ; Humerus ; Korea ; Leukocyte Count ; Lymphocyte Count ; Lymphocytes ; Medical Records ; Monocytes ; Osteosarcoma ; Retrospective Studies ; Survival Rate ; Tibia ; Treatment Outcome

OBJECTIVE: To determine whether diffusion kurtosis imaging (DKI) is effective in monitoring tumor response to neoadjuvant chemotherapy in patients with osteosarcoma. MATERIALS AND METHODS: Twenty-nine osteosarcoma patients (20 men and 9 women; mean age, 17.6 ± 7.8 years) who had undergone magnetic resonance imaging (MRI) and DKI before and after neoadjuvant chemotherapy were included. Tumor volume, apparent diffusion coefficient (ADC), mean diffusivity (MD), mean kurtosis (MK), and change ratio (ΔX) between pre- and post-treatment were calculated. Based on histologic response, the patients were divided into those with good response (≥ 90% necrosis, n = 12) and those with poor response (< 90% necrosis, n = 17). Several MRI parameters between the groups were compared using Student's t test. The correlation between image indexes and tumor necrosis was determined using Pearson's correlation, and diagnostic performance was compared using receiver operating characteristic curves. RESULTS: In good responders, MDpost, ADCpost, and MKpost values were significantly higher than in poor responders (p < 0.001, p < 0.001, and p = 0.042, respectively). The ΔMD and ΔADC were also significantly higher in good responders than in poor responders (p < 0.001 and p = 0.01, respectively). However, no significant difference was observed in ΔMK (p = 0.092). MDpost and ΔMD showed high correlations with tumor necrosis rate (r = 0.669 and r = 0.622, respectively), and MDpost had higher diagnostic performance than ADCpost (p = 0.037) and MKpost (p = 0.011). Similarly, ΔMD also showed higher diagnostic performance than ΔADC (p = 0.033) and ΔMK (p = 0.037). CONCLUSION: MD is a promising biomarker for monitoring tumor response to preoperative chemotherapy in patients with osteosarcoma.
Bone Neoplasms ; Diffusion ; Drug Therapy ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Necrosis ; Osteosarcoma ; ROC Curve ; Tumor Burden

Multidrug resistance (MDR) is one of the major obstacles in cancer chemotherapy. Our previous study has shown that icariin could reverse MDR in MG-63 doxorubicin-resistant (MG-63/DOX) cells. It is reported that icariin is usually metabolized to icariside II and icaritin. Herein, we investigated the effects of icariin, icariside II, and icaritin (ICT) on reversing MDR in MG-63/DOX cells. Among these compounds, ICT exhibited strongest effect and showed no obvious cytotoxicity effect on both MG-63 and MG-63/DOX cells ranging from 1 to 10 μmol·L. Furthermore, ICT increased accumulation of rhodamine 123 and 6-carboxyfluorescein diacetate and enhanced DOX-induced apoptosis in MG-63/DOX cells in a dose-dependent manner. Further studies demonstrated that ICT decreased the mRNA and protein levels of multidrug resistance protein 1 (MDR1) and multidrug resistance-associated protein 1 (MRP1). We also verified that blockade of STAT3 phosphorylation was involved in the reversal effect of multidrug resistance in MG-63/DOX cells. Taken together, these results indicated that ICT may be a potential candidate in chemotherapy for osteosarcoma.
ATP Binding Cassette Transporter, Subfamily B ; drug effects ; genetics ; metabolism ; Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Cell Line, Tumor ; Cell Survival ; drug effects ; Dose-Response Relationship, Drug ; Doxorubicin ; metabolism ; pharmacology ; toxicity ; Drug Resistance, Multiple ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; Flavonoids ; pharmacology ; Gene Expression Regulation, Neoplastic ; drug effects ; Humans ; Multidrug Resistance-Associated Proteins ; drug effects ; genetics ; metabolism ; Osteosarcoma ; drug therapy ; metabolism ; pathology ; Phosphorylation ; drug effects ; Rhodamine 123 ; metabolism ; STAT3 Transcription Factor ; antagonists & inhibitors ; metabolism ; Triterpenes ; pharmacology

BACKGROUND: By estimating the survival rates and exploring prognostic factors in pediatric patients with relapsed or progressed solid tumors, our purpose was to generate background data for future studies. METHODS: We reviewed the medical records of 258 patients with solid tumors who experienced relapse/progression and received subsequent salvage treatment between 1996 and 2016. RESULTS: A total of 60 patients remained progression-free during first-line salvage treatment, while the remaining 198 patients experienced relapse/progression again; 149 underwent second-line salvage treatment. A total of 76 patients underwent high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT), and 44 patients received allogeneic SCT. The 10-year progression-free survival (PFS) and overall survival (OS) from relapse/progression were 18.4% ± 2.7% and 24.5% ± 3.0%, respectively. Survival rates were relatively higher in patients with anaplastic ependymoma, initially non-high-risk neuroblastoma, osteosarcoma, Wilms tumor and retinoblastoma. A multivariate analysis showed that relapse/progression during initial treatment, metastatic relapse/progression, and impossible debulking surgery were independent poor prognostic factors for both PFS and OS. Patients who exhibited a complete response or partial response during conventional salvage treatment showed significantly higher survival after SCT than those with stable disease or progressive disease (10-year OS: 54.8% ± 7.0% vs. 7.0% ± 3.5%, P < 0.001). CONCLUSION: The prognosis of relapsed/progressed pediatric solid tumors still remains unsatisfactory. New, effective treatment strategies are needed to overcome limitations of current approaches. Hopefully, the background data generated herein will be used in future clinical trials involving patients with relapsed/progressed solid tumors.
Adolescent* ; Child* ; Disease-Free Survival ; Drug Therapy ; Ependymoma ; Humans ; Medical Records ; Multivariate Analysis ; Neuroblastoma ; Osteosarcoma ; Prognosis ; Recurrence ; Retinoblastoma ; Salvage Therapy ; Stem Cell Transplantation ; Survival Rate ; Wilms Tumor

OBJECTIVES: In order to assess clinical behavior, response to treatment, and factors influencing prognosis of Korean patients with osteosarcoma of the jaws (OSJ). MATERIALS AND METHODS: A retrospective study of clinical, and pathological records of 26 patients with OSJ treated at the Department of Oral and Maxillofacial Surgery in Yonsei University Dental Hospital from 1990 to March 2017. RESULTS: Of 26 patients, there were 9 men (34.6%) and 17 women (65.4%). Twenty-one of 26 patients had osteosarcoma of the mandible, and 5 of 26 patients had osteosarcoma of the maxilla. The histopathology of OSJ is highly variable, ranging from chondroblastic type (6 out of 26), osteoblastic type (10 out of 26), fibroblastic type (2 out of 26), to the rare variants like mixed type, small cell osteosarcoma types and more. All patients underwent gross total excision and only a few patients underwent neoadjuvant chemotherapy. Postoperative chemotherapy was given to most of the patients as adjuvant treatment or in combination with radiotherapy. The overall survival rate was 73.1% with an overall 2-year survival rate of 83.3%. The overall 5-,10-,15-year survival rates in this study were 73.5%, 73.5%, 49%, respectively. Using Kaplan-Meier analysis with log rank tests, the size of tumor (T-stage), and resection margins were found to affect the survival rate significantly. The chemotherapy was not significantly associated with improved survival rate. CONCLUSION: Surgical resection with a clear margin is the most important factor in disease survival. The role of chemotherapy and radiotherapy in OSJ remains controversial, and deserves further studies.
Chondrocytes ; Drug Therapy ; Female ; Fibroblasts ; Humans ; Jaw* ; Kaplan-Meier Estimate ; Male ; Mandible ; Maxilla ; Osteoblasts ; Osteosarcoma* ; Prognosis ; Radiotherapy ; Retrospective Studies ; Surgery, Oral ; Survival Rate