Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. The purpose of this study is to explore the regulatory mechanism of LINC01116 in osteosarcoma metastasis and its potential association with the urea cycle and chemoresistance. Transcriptomic profiling was performed, and the results were validated by qRT-PCR in 6 paired osteosarcoma and adjacent non-tumor tissues. Functional assays including in vivo xenograft models were used to verify the effect of LINC01116 on osteosarcoma cell proliferation. RNA-protein interaction studies and ChIRP-MS assays were conducted to confirm the binding between LINC01116 and CPS1.LINC01116 was significantly upregulated in metastatic osteosarcoma lesions. Silencing LINC01116 inhibited osteosarcoma cell proliferation both in vitro and in vivo. Mechanistically, LINC01116 directly binds to CPS1 -the rate-limiting enzyme of the urea cycle, which was confirmed by ChIRP-MS. Perturbing the LINC01116/CPS1 axis reduced citrulline levels, indicating impaired urea cycle function. Additionally, CPS1 silencing enhanced osteosarcoma cell sensitivity to cisplatin. This study identifies a novel LINC01116/CPS1 axis that drives osteosarcoma metastasis by regulating the urea cycle. Targeting this axis can sensitize osteosarcoma to cisplatin treatment, which highlights its potential as a therapeutic target for osteosarcoma.

Osteochondral defect (OCD) involves cartilage and subchondral bone damage, often accompanied by a reactive oxygen species (ROS)-rich inflammatory microenvironment that impairs tissue regeneration. Thus, developing a ROS-scavenging scaffold enabling integrated cartilage-bone regeneration is critical. We designed nano-cerium oxide/tanshinone IIA/nano-hydroxyapatite@dual-network hydrogel (nCeO2/TAN/nHA@DN) using polyvinyl alcohol (PVA) and peptides: nCeO2 scavenges ROS, TAN (cartilage layer) and nHA (bone layer) promote chondrocyte and osteoblast activities. Verified via 3D printing, kits, and transcriptome sequencing, the hydrogel showed excellent mechanical properties (withstanding 0.4 MPa at 80% recompression), printability, biocompatibility, and ROS-scavenging capacity. Mechanistically, nCeO2 inhibited IL-17A/MMP-3; TAN upregulated FMOD to inhibit ERK1/2 phosphorylation, regulate Bcl-2/BAX, and enhance COL2A1; and nHA activated PI3K-AKT phosphorylation and upregulated COL1. In vivo rabbit models confirmed its efficacy in integrated OCD repair. Integrating antioxidant and biological strategies is effective for inflammatory OCD repair with clinical potential.

BACKGROUND:There is no standard systemic therapy for unresectable chondrosarcoma. The purpose of this study is to explore the efficacy of combination therapy with an anti-PD-1 antibody and anlotinib in patients with advanced chondrosarcoma. METHODS:Patients with dedifferentiated or high-grade conventional chondrosarcoma were eligible. Anlotinib was administered at 12 mg orally once a day from day 1 to 14 every 3 weeks in all participants. In the combination treatment arm, patients received an additional anti-PD-1 antibody at 200 mg every 3 weeks. The primary endpoint was the 6-month progression-free survival rate (PFSR). Biomarker analyses for therapeutic effectiveness were conducted. FINDINGS:70 patients (32 with dedifferentiated and 38 with conventional chondrosarcoma) were enrolled in the study. After a medium follow-up of 15.6 months, combination treatment showed significantly improved outcomes compared to anlotinib alone in the entire population, with a higher 6-month PFSR (60.0% versus 31.4%). The PFS-event inverse probability weighting adjusted Cox model evaluation also revealed a significant benefit of combination treatment (hazard ratio = 0.14, 95% confidence interval [CI]: 0.07-0.30, p < 0.001). Patients with dedifferentiated chondrosarcoma benefited the most from the combination treatment, with improvements in objective response rate (33.3% versus 9.1%), 6-month PFSR (57.1% versus 9.1%), median PFS (7.0 months versus 3.8 months), and 1-year overall survival rate (42.9% versus 18.2%). Effector memory T cells were significantly associated with treatment response (p < 0.001). CONCLUSIONS:The combination treatment demonstrated promising efficacy in advanced chondrosarcoma, particularly for dedifferentiated cases (ClinicalTrials.gov: NCT05193188). FUNDING:This trial was supported by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

The repair and reconstruction of bone defects remain a challenge in orthopedics. Inadequate mechanical qualities, poor biocompatibility, and insufficient osteoconductivity are some of the issues facing current bone healing materials. Better materials that can replicate the composition and functionality of natural bone, promote quick and full healing, and reduce the likelihood of rejection and infection are desperately needed. Bone tissue engineering, combining biomaterial scaffolds and pro-osteogenic drugs, provides support in the repair and regeneration of bone defects. The development of an effective scaffold for bone defect repair is an urgent clinical need. The present study investigates the feasibility of using microspheres based on α-tricalcium phosphate and fibroin as an osteoconductive matrix and a carrier for controlled local delivery of the E7BMP-2 peptide, in which the E7 domain confers a calcium chelation property, while the BMP-2 mimicking peptide induces bone formation. We prepared α-tricalcium phosphate/silk fibroin (α-TCP/SF) microspheres through a high voltage electric field based on the protocol of α-TCP/SF bone cement slurry. This α-TCP/SF microspheres-based system was designed for delivery vehicles of the modified BMP-2 peptide by the E7 domain to realize sustainable and steady release of the peptide. In vitro cell tests and the experimental model of cranial bone defects in rats were used to investigate the pro-osteogenic benefits. The results demonstrated that the E7BMP-2 peptide-bound microspheres functioned as a sustained release system for the peptide and enhanced osteogenic differentiation of bone marrow mesenchymal stem cells in rat calvarial defects. Additionally, toxicity studies showed that microspheres have good biocompatibility and safety. Thus, these E7BMP-2 peptide-bound α-TCP/SF microspheres provide a promising therapeutic strategy for the treatment of bone defects.

Circular RNAs (circRNAs) are non-coding RNAs that exist naturally in various eukaryotic organisms. The majority of circRNAs are produced through the splicing of exons, although there are a limited number that are generated through the circularization of introns. Studies have shown that circRNAs play an irreplaceable role in the pathogenesis, disease progression, diagnosis, and targeted therapy of motor system tumors (osteosarcoma), metabolic diseases (osteoporosis), and degenerative diseases (osteonecrosis of the femoral head, osteoarthritis, intervertebral disc degeneration). This review summarizes the advancements in circRNA detection techniques and the research progress of circRNAs in orthopedic diseases.

Circular RNAs (circRNAs) are a class of non-coding RNAs which take part in the regulation of the initiation and development of different types of cancer. Numerous studies have demonstrated that circRNAs are involved in the progression of osteosarcoma (OS) as well. Thus, we put our emphasis on the exploration of crucial circRNAs in the process of OS initiation and progression. Using RNA sequencing, we found that circSATB2 was highly expressed in OS tissues compared with adjacent normal tissues. Then, we confirmed the high expression of circSATB2 in OS cell lines and OS tissues and its high expression was related to poor prognosis of OS patients. Functional experiments exhibited that circSATB2 promoted OS proliferation and migration in vitro, primary OS model and OS lung metastasis model showed that circSATB2 aggravated OS progression in vivo. Mechanistically, circSATB2 was found to promote OS progression through sponging miR-661 and FUS regulating the mRNA of ZNFX1. Therefore, circSATB2 could act as a prognostic marker and a therapeutic target for osteosarcoma in the future.

Objective To explore the imaging features,clinical outcome,and prognosis of indeterminate pulmonary nodules(IPN)in patients with high-grade soft tissue sarcoma.Methods A retrospective study of 82 patients with high-grade soft tissue sarcoma who have IPNs.The clinical characteristics,imaging features of IPN,and survival of patients were analyzed with statistical software.Results The IPN size of 82 patients was 6.453±0.864 mm.IPN diameter,shape,density,and nodule discovery interval may be CT imaging features related to malignancy tendency.Age(HR=1.047,95%CI:1.007-1.088)and interval between each nodule discovery(HR=3.194,95%CI:1.052-9.694)are independent factors that affect the survival of patients with malignant IPN.Conclusion The imaging features of chest CT may provide important guidance for determining the nature and survival prognosis of benign and malignant nodules.

FRS2 has demonstrated oncogenic roles in various malignancies, including liposarcoma and giant cell tumor of bone. However, its role in osteosarcoma remains less understood, and the upstream regulatory molecules influencing FRS2 remain unclear. This study aims to explore the clinical implications and biological function of FRS2 in osteosarcoma, and the potential regulatory microRNAs (miRNAs) governing its expression. Our study indicated significant upregulation of FRS2 in osteosarcoma cells and tissues by Western blotting and immunohistochemical staining. Elevated FRS2 expression correlated positively with increased angiogenesis and poor prognosis, possibly serving as an independent prognostic indicator for osteosarcoma patients. Functional assays revealed that attenuating FRS2 in osteosarcoma cells could mitigate proliferation, migration, and angiogenesis of vascular endothelial cells. Further investigations revealed that miR-429 and miR-206 directly targeted FRS2, exerting a negative regulation on its expression. Furthermore, FRS2 played a role in repressing osteosarcoma advancement influenced by miR-429 or miR-206. In summary, FRS2, influenced by miR-429 and miR-206, emerges as a promising therapeutic candidate for antiangiogenic osteosarcoma treatments.

Background/Objective Brain metastasis in osteosarcoma (BMO) is rare and its clinical characteristics are often buried among studies on brain metastasis of bone and soft tissue sarcomas. The aim of the present study was to summarize the incidence, clinical characteristics, treatment and outcomes of patients with BMO.Methods This retrospective study included 7 patients with BMO who received treatment in our center between 2005 and 2019. The clinical medical records of the 7 patients, together with data of 70 BMO patients published in 33 articles and retrieved by means of PubMed and Medline, were analyzed, retrospectively.Results Data analysis of the 97 BMO patients showed a high correlation between the interval from the primary diagnosis to BMO occurrence and the interval from the primary diagnosis to prior metastases. Multivariate analysis showed that chemotherapy, radiotherapy and surgery were three main factors affecting the overall survival of BMO patients (HR = 0.427; HR = 0.372; HR = 0.296). Surgery combined with chemotherapy or radiotherapy offered a better overall survival than surgery alone.Conclusion Patients with BMO may obtain survival benefits from regular neuroimaging and early aggressive multi-disciplinary interventions including surgical resection, postoperative radiotherapy and chemotherapy.Synopsis This is a retrospective study describing the characteristics of metastasic intervals, locations, clinical features and prognosis in 97 patients with brain metastasis of osteosarcoma (BMO). Multivariate analysis showed that chemotherapy was effective as surgery and radiotherapy for the treatment of BMO. Our findings emphasize the importance of regular neuroimaging and early aggressive multi-disciplinary interventions including surgical resection, postoperative radiotherapy and chemotherapy.

Objective:To compare outcomes between standardized and misdiagnosis and mistreatment of osteosarcoma.Methods:A retrospective analysis of patients with high-grade osteosarcoma who received appropriate surgical treatment and chemotherapy (299 cases, control group) and those who were misdiagnosed (benign or infective) and received mistreatment (23 cases, study group) between January 2009 and December 2021. Gender, age, first operation mode, recurrence time, recurrence interval, metastasis time, metastasis interval, total survival time (months), survival status in the two group and tumor site reoperation mode in the study group were statistically analyzed. Further, chi-square test was performed for comparison of the clinical between two groups. The survival analysis was performed using Kaplan-Meier test and Log-rank test.Results:All the 322 patients were followed up. In the control group, the average follow-up time was 42 months (1-137 months), the average age was 24 years (3-80 years), male 184 cases, female 115 cases, and limb salvage rate was 85.3% (255/299). Seven patients underwent amputation, and the amputation rate was 17.7% (44/299). The recurrence rate was 8.4% (25/299), the average recurrence interval was 22.8 months (7-36 months), and the metastasis rate was 28.1% (85/299), the average metastasis time was 32.7 months (0-58 months). In the study group, the average of follow-up time was 30 months (9-117 months), the average age was 36 years (5-67 years), 17 males and 6 females. Among them, eleven patients were treated with limb salvage in the second stage, and the limb salvage rate was 47.8% (11/23). Seven patients underwent amputation, and the amputation rate was 30.4% (7/23). The recurrence rate was 26.1% (6/23), the average recurrence interval was 11 months (1-42 months), and the metastasis rate was 43.4% (10/23), the average metastasis time was 20.3 months (1-44 months). The 5-year survival rate was 50.7% in the study group and 56.1% in the control group. There was no significant difference between the two groups (χ 2=0.09, P=0.760). Conclusion:The overall prognosis of patients with high-grade osteosarcoma who receive active treatment after mistreatment is similar to that of patients with standardized treatment, but the recurrence and metastasis rate is higher, the recurrence time is earlier, and the amputation rate is higher.

The prognosis of lung metastatic osteosarcoma (OS) remains disappointing. siRNA-based gene silencing of VEGFR2 is a promising treatment strategy for lung metastatic OS, but there is a lack of safe and efficient delivery systems to encapsulate siRNAs for in vivo administration. This study presented a synthetic biological strategy that remolds the host liver with synthesized genetic circuits for efficient in vivo VEGFR2 siRNA delivery. After being taken-up by hepatocytes, the genetic circuit (in the form of a DNA plasmid) reprogrammed the liver to drive the autonomous intrahepatic assembly and encapsulation of VEGFR2 siRNAs into secretory small extracellular vesicles (sEVs), thus allowing for the transport of self-assembled VEGFR2 siRNAs towards the lung. The results showed that our strategy was superior to the positive medicine (Apatinib) for OS lung metastasis in terms of therapeutic efficacy and toxic adverse effects and may provide a feasible and viable therapeutic solution for lung metastatic OS.

Background Osteosarcoma (OS) is the most common primary malignant bone tumors in children and adolescents. Large numbers of studies have focused on the long non-coding RNA (lncRNA) that plays essential roles in the progression of osteosarcoma. Nevertheless, the functions and underlying mechanisms of LncRNA NDRG1 in osteosarcoma remain unknown. Methods Differentially expressed lncRNAs between osteosarcoma and adjacent normal tissues were identified through RNA sequencing. The role of LncRNA NDRG1 in osteosarcoma proliferation and metastasis were investigated through in vitro and in vivo functional experiments. The interaction between LncRNA NDRG1 and miR-96-5p was verified through bioinformatic analysis and luciferase reporter assay. Regulation relationship between LncRNA NDRG1 and miR-96-5p was further evaluated by the rescue experiments. Additionally, the changes in the expression of epithelial-mesenchymal transition (EMT) and the PI3K/AKT pathway were verified by Western blot. Results LncRNA NDRG1 was up-regulated in osteosarcoma cell lines and tissues and the expression of LncRNA NDRG1 was correlated with the overall survival of osteosarcoma patients. Functional experiments exhibited that LncRNA NDRG1 aggravated osteosarcoma proliferation and migration in vitro; meanwhile, animals experiments showed that LncRNA NDRG1 promoted osteosarcoma growth and metastasis in vivo. Mechanistically, LncRNA NDRG1 was found to aggravate osteosarcoma progression and regulate the PI3K/AKT pathway by sponging miR-96-5p. Conclusions LncRNA NDRG1 aggravates osteosarcoma progression and regulates the PI3K/AKT pathway by sponging miR-96-5p. Therefore, LncRNA NDRG1 could act as a prognostic marker and a therapeutic target for osteosarcoma in the future.

Background. Osteosarcoma (OS) is the most common primary aggressive sarcoma of bone, with massive aberrant expression of oncogenes related to the development of OS. RALA, a kind of small Ras-like guanosine triphosphatases, has been identified as a potential therapeutic target in several types of tumor, but its role in OS remains largely unknown. Methods. Abnormal expression of RALA was proven in the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and RNA-sequence of samples and cell lines. The role of RALA in OS was analyzed in terms of DNA methylation, immune cell infiltration, and patient survival. The cancer-promoting effect of RALA was demonstrated in cell lines and xenograft osteosarcoma models. A prognostic scoring model incorporating RALA as an indicator was established with the clinical samples that we collected. Results. The results showed that RALA was highly expressed in human OS tissues and cell lines. Survival analysis demonstrated that RALA was the sole independent risk factor for poor overall survival and disease-free survival in OS patients and impacted the proportion of infiltrating immune cells and DNA methylation in the OS tumor microenvironment. By gene-gene interaction analysis, we found that the expression of RALA was highly correlated to the expression of ABCE1. Similar to RALA, upregulated ABCE1 is correlated with poor survival outcome of OS patients. In addition, the functional experiment demonstrated that higher expression of RALA promoted the proliferation, migration, and invasion of OS cells. In vivo results were similar with the in vitro results. We examined m6a methylation-related genes and found that m6A methylation is responsible for the abnormal expression of RALA. Finally, the prognostic prediction model of RALA could be used to predict the long-term outcome of OS patients. Conclusions. We identified RALA as an oncogene in OS, and RALA upregulation in a concerted manner with ABCE1 was significantly associated with worse outcomes of OS patients. Targeting RALA may prove to be a novel target for OS immunotherapy in future clinical practice.

软骨肉瘤是一种具有多种形态特征和临床表现的恶性软骨源性肿瘤,约占骨原发恶性肿瘤的20％[1].临床可分为原发性软骨肉瘤和继发性软骨肉瘤,原发软骨肉瘤占总数85％～90％[2].其特点为形成软骨基质且生长缓慢.软骨肉瘤好发于长骨和骨盆[3],肩胛骨比较少见.软骨肉瘤对放疗、化疗均不敏感,手术切除为其首选治疗方法.由于肩胛骨的解剖特点,目前肩胛骨手术切除后如何维持肩关节功能仍存在很大挑战.本文报道1例52岁女性肩胛骨软骨肉瘤患者,切除后利用3D打印假体重建肩关节功能,报告如下.

骨巨细胞瘤是一种常见的骨原发性肿瘤之一,具有局部侵袭性.多发于长骨干骺端,膝关节周围最常见,目前其组织起源尚不清楚.因其生物学行为上不确定性和较高复发率,临床上骨巨细胞瘤的诊断、治疗及预后仍面临着许多困难.随着基因学、药物学、材料学、外科技术等发展,骨巨细胞瘤的治疗方式逐渐增多,各具有其优缺点.本文总结了骨巨细胞瘤手术治疗、药物治疗、放疗、栓塞治疗进展,以期为临床工作中骨巨细胞瘤的治疗选择提供参考.

OBJECTIVE:To observe the efficacy and complications of one-stage tumor resection to treat primary sacral neurogenic tumors and to discuss some details in the clinically relevant anatomy.METHODS:A retrospective analysis of 26 patients with neurogenic turors of the sacral spine who were surgically treated from January 2001 to January 2018, including 16 males and 10 females, aged from 21 to 69 years old with an average age of (39.3±10.9) years old. The courses of diseases ranged from 3 to 56 months with an average of (17.9±10.1) months. The diameters of presacral components ranged from 3.3 to 19.6 cm with an average of (8.7±4.1) cm. The proximal margin of presacral lesions was above the L5S1 level in 6 cases, and lower than L5S1 in 20 cases. A posterior incision approach for one-stage complete resection of the tumor was used firstly, and an anterior approach was combined when necessary. Spinal-pelvic reconstruction with the modified Galveston technique was also carried out in relevant cases. Whether to preserve the tumor-involved nerve roots depended on the situation during the operation. The operation time, intraoperative blood loss, pain relief, and complications were recorded. The lumbosacral spine stability and sacral plexus neurological function were evaluated during postoperative follow-up, and local recurrence and distant metastasis were examined as well.RESULTS:Total excision was achieved in all 26 patients, with an operation time of (160.4±35.3) mins and an intraoperative blood loss of (1 092.3±568.8) ml. Tumors have been removed via a posterior-only approach in 21 cases and via combined anterior/posterior approaches in 5 cases. The diameter of presacral masses components ranged from 11.3 to 19.6 cm with an average of (15.1±3.2) cm in patients with combined anterior/posterior approaches, and ranged from 3.3 to 10.9 cm with an average of (7.2±2.4) cm in patients with a posterior-only approach. Five of the six patients whose proximal margin of presacral masses was above the L5S1 level adopted combined anterior/posterior approaches, and 20 patients lower than the L5S1 level adopted the posterior-only approach. All the patients were followed up for 6 to 82 months with an average of(45.4±18.2)months. Postoperative lumbosacral pain and lower extremity radicular pain were significantly relieved, and sensation, muscle strength and bowel and bladder function were also improved to varying degrees. The postoperative early complications included superficial wound infection in 1 case and cerebrospinal fluid leakage in 2 cases. Pathology confirmed 17 cases of schwannoma, 7 cases of neurofibroma and 2 cases of malignant schwannoma. Local recurrence was observed in two cases of benign neurogenic tumors. One patient with a malignant nerve sheath tumor had lung metastasis, who died 20 months after the operation. In 17 cases of upper sacral neurogenic tumors, 4 cases did not undergo spinal-pelvic reconstruction with internal fixation, of which 2 cases suffered from postoperative segmental instability. Tumor-involved nerve roots were resected during surgery in 7 cases. One of these patients who had S2 and S3 nerve roots sacrificed simultaneously had an impaired bladder and bowel function postoperatively, and did not recover completely. In the other 6 cases, the neurological function was not damaged obviously or recovered well.CONCLUSION:The posterior approach can directly expose the lesions, and it is also convenient to deal with nerve roots and blood vessels. The operation time, intraoperative blood loss, degree of symptom relief, complication rate, and recurrence and metastasis rate can be controlled at an appropriate level. It is a safe and effective surgical approach. When the upper edge of the presacral mass is higher than the L5S1 level or the diameter of the presacral mass exceeds 10 cm, an additional anterior approach should be considered. The stress between the spine and pelvis is high, and internal fixation should be used to restore the mechanical continuity of the spine and pelvis during resection of neurogenic tumors of the high sacral spine. Most of the parent nerve roots have lost their function. Resection of a single parent nerve root is unlikely to cause severe neurological dysfunction, while the adjacent nerve roots have compensatory functions and should be preserved as much as possible during surgery.

目的 比较骨干骨肉瘤保肢手术生物重建与假体重建的肢体功能和患者满意度.方法 回顾性分析2015年1月至2020年10月,我院收治的26例骨干骨肉瘤患者.年龄4～53岁,平均(18.35±12.81)岁.性别差异无统计学意义.肿瘤均位于四肢长干骨,根据Ennking肿瘤分期[1],ⅡA期14例,ⅡB期8例,Ⅲ期4例.根据重建方法分为生物重建组(18例)和定制假体重建(8例).生物重建组18例中自体腓骨重建13例,大段异体骨重建5例.结果 随访3～70个月,平均(31.15±14.13)个月.ISOLS总分:定制假体组(24.00±2.69)分优于生物重建组(17.11±1.70)分,P=0.037;各单项比较中,仅患者心理满意度方面定制假体组(3.63±0.42)优于生物重建组(2.28±0.32),P<0.05,而其它单项两者比较差异无统计学意义.生物重建组出现骨折、不愈合、感染及局部复发并发症8例次,定制假体组出现松动、感染及局部复发并发症3例次,两者差异无统计学意义.结论 骨干骨肉瘤保肢治疗选择不同重建方式对预后无明显影响,但定制假体重建功能优于生物重建,可较快恢复行走及持物功能.