Targeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer.

Therapeutic resistance represents a bottleneck to treatment in advanced gastric cancer (GC). Ferroptosis is an iron-dependent form of non-apoptotic cell death and is associated with anti-cancer therapeutic efficacy. Further investigations are required to clarify the underlying mechanisms. Ferroptosis-resistant GC cell lines are constructed. Dysregulated mRNAs between ferroptosis-resistant and parental cell lines are identified. The expression of SOX13/SCAF1 is manipulated in GC cell lines where relevant biological and molecular analyses are performed. Molecular docking and computational screening are performed to screen potential inhibitors of SOX13. We show that SOX13 boosts protein remodeling of electron transport chain (ETC) complexes by directly transactivating SCAF1. This leads to increased supercomplexes (SCs) assembly, mitochondrial respiration, mitochondrial energetics and chemo- and immune-resistance. Zanamivir, reverts the ferroptosis-resistant phenotype via directly targeting SOX13 and promoting TRIM25-mediated ubiquitination and degradation of SOX13. Here we show, SOX13/SCAF1 are important in ferroptosis-resistance, and targeting SOX13 with zanamivir has therapeutic potential.

MRI-Based Radiomics and Delta-Radiomics Models of the Patella Predict the Radiographic Progression of Osteoarthritis: Data From the FNIH OA Biomarkers Consortium.

RATIONALE AND OBJECTIVES: To analyse the MRI-based radiomics and delta-radiomics features to establish radiomics models for predicting the radiographic progression of osteoarthritis (OA). MATERIALS AND METHODS: The data used in this research come from the dataset of the FNIH Biomarker Consortium Project within the Osteoarthritis Initiative (OAI). 565 participants randomly divided into training and validation groups at a 7:3 ratio. The training cohort consisted of 395 participants and included 202 cases. The validation cohort consisted of 170 participants and included 87 cases. Least absolute shrinkage and selection operator (LASSO) was used for feature selection. Support vector machine (SVM) was used to establish radiomics models and clinical and biomarker models for predicting the radiographic progression of OA. The predictive ability of the model was evaluated by the area under the curve (AUC). RESULTS: The baseline, 24 M, Delta, and two combination radiomics models (Baseline and Delta, 24 M and Delta) all showed good predictive performance in the training and validation cohorts, with the combination model exhibiting the best performance. In the training cohort, the AUCs were 0.851 (95% CI: 0.812-0.890), 0.825 (95% CI: 0.784-0.865), 0.804 (95% CI: 0.761-0.847), 0.892 (95% CI: 0.860-0.924) and 0.884 (95% CI: 0.851-0.917), respectively. The AUCs in the validation cohort were 0.741 (95% CI: 0.667-0.814), 0.786 (95% CI: 0.716-0.856), 0.745 (95% CI: 0.671-0.819), 0.781 (95% CI: 0.711-0.851) and 0.802 (95% CI: 0.736-0.869), respectively. As compared, the clinical and biomarker models have AUC < 0.74. The DeLong test showed that the predictive performance of the radiomics models in the training and validation cohorts was significantly better than that of the clinical and biomarker models (P < 0.001). CONCLUSION: The MRI-based radiomics models of the patella all showed good predictive performance performed better than the clinical and biomarker models in predicting the radiographic progression of OA. Delta radiomics can improve the predictive performance of the single time model, the combined model of 24 M and Delta provided the best predictive performance.

TRIM54 alleviates inflammation and apoptosis by stabilizing YOD1 in rat tendon-derived stem cells.

Tendinopathy is a disorder of musculoskeletal system that primarily affects athletes and the elderly. Current treatment options are generally comprised of various exercise and loading programs, therapeutic modalities, and surgical interventions and are limited to pain management. This study is to understand the role of TRIM54 (tripartite motif containing 54) in tendonitis through in vitro modeling with tendon-derived stem cells (TDSCs) and in vivo using rat tendon injury model. Initially, we observed that TRIM54 overexpression in TDSCs model increased stemness and decreased apoptosis. Additionally, it rescued cells from tumor necrosis factor α-induced inflammation, migration, and tenogenic differentiation. Further, through immunoprecipitation studies, we identified that TRIM54 regulates inflammation in TDSCs by binding to and ubiquitinating YOD1. Further, overexpression of TRIM54 improved the histopathological score of tendon injury as well as the failure load, stiffness, and young modulus in vivo. These results indicated that TRIM54 played a critical role in reducing the effects of tendon injury. Consequently, these results shed light on potential therapeutic alternatives for treating tendinopathy.

Surgical resection of soft tissue metastasis in cancers: A single-center study of 77 cases over a 7-year period.

INTRODUCTION: Soft tissue metastasis (STM) of cancers, encompassing skeletal muscle and subcutaneous tissue metastasis, is less common due to unique homeostatic conditions. With longer life expectancy and the advent of new imaging modalities, clinical physicians will increasingly encounter and manage such cases. This study retrospectively reviewed cases of STM in visceral cancers who underwent surgery at Fudan University Shanghai Cancer Center over a 7-year period. METHODS: Data were collected through a comprehensive review of medical records, including demographic variables, primary tumor characteristics, surgical data, tumor pathology, and outcomes. Survival analysis was performed using Kaplan-Meier curves. RESULTS: The study included 77 cases with a median follow-up period of 854 days. The most common primary tumor sites were the lung (11) and breast (10). The abdominal wall was the most frequent site of metastasis. The combination of visceral metastasis, age over 52 years, and a history of primary tumor correlates with a poorer prognosis. Surgical-related metastases are associated with a higher degree of differentiation. Additionally, we have identified a better prognosis for patients with cancer of unknown primary (CUP) exhibiting potential resectable soft tissue metastases. CONCLUSION: The combination of visceral metastasis, age over 52 years, and a history of primary tumor suggest a poorer prognosis. While no significant impact on survival was observed for patients with lymph node metastasis. Surgical-related metastases are associated with a higher degree of differentiation. CUP patients with potentially resectable soft tissue metastases should be considered for surgical intervention.

IOX1 epigenetically enhanced photothermal therapy of 3D-printing silicene scaffolds against osteosarcoma with favorable bone regeneration.

Osteosarcoma (OS) is the third most common malignancy in adolescence. Currently, the treatments of OS confront great obstacles of tumor recurrence and critical bone defects after surgery, severely affecting the survival rates and living qualities of patients. Hence, it is urged to develop distinct biomaterials with both efficient tumor therapeutic and osteogenic functions. Although photothermal therapy (PTT) has aroused expanding interest, characterizing negligible invasiveness and high spatiotemporal adjustment, few studies discussed its drawbacks, such as thermal injury to adjacent normal tissue and exceeded laser power density, implying that focusing on sensitizing OS to PTT instead of simply elevating the laser power density may be a fresh way to enhance the PTT efficacy and attenuate the side/adverse effects. Herein, we successfully constructed 3D-printing silicene bioactive glass scaffolds with preferable PTT efficacy at the second near-infrared (NIR-II) biowindow and outstanding osteogenic biofunctions owing to the release of bioactive elements during degradation. Impressively, a histone demethylase inhibitor, IOX1, was introduced before PTT to sensitize OS to thermal therapy and minimize the side/adverse effects. This work offered a distinctive paradigm for optimizing the PTT efficacy of osteogenic scaffolds against OS with epigenetic modulation agents.

Does primary tumor resection improve survival for patients with sarcomas of pelvic bones, sacrum, and coccyx who have metastasis at diagnosis ?

BACKGROUND: Recent studies demonstrated that primary tumor resection (PTR) improves survival of patients with metastatic bone sarcomas. However, it remains quite unclear regarding the role of PTR in the treatment of sarcomas of pelvic bones with synchronous metastasis at diagnosis. METHODS: Using the Surveillance, Epidemiology, and End Results Program, we enrolled a total of 385 patients with sarcomas of pelvic bones, sacrum, and coccyx who have metastasis at initial diagnosis, including 139 patients with osteosarcoma, 176 with Ewing sarcoma, and 70 with chondrosarcoma. Association between PTR and disease-specific survival (DSS) were investigated using the univariable and multivariable Cox regression models. Hazard ratio (HR) and 95% confidence interval (CI) were reported. Representative institutional PTR strategies and clinical outcomes for patients with metastatic pelvic sarcomas from our cancer center were displayed. RESULTS: The usage rate of PTR was 28.1% (39/139) in osteosarcoma, 13.6% (24/176) in Ewing sarcoma, and 41.4% (29/70) in chondrosarcoma with synchronous metastatic lesions. PTR was not associated with an improved DSS for metastatic pelvic osteosarcoma (HR = 0.686, 95% CI = 0.430 ~ 1.094, P = 0.113) and Ewing sarcoma (HR = 0.580, 95% CI = 0.291 ~ 1.154, P = 0.121). The use of PTR was associated with an improved DSS for metastatic pelvic chondrosarcoma (HR = 0.464, 95% CI = 0.225 ~ 0.954, P = 0.037). CONCLUSION: Primary lesion resection may provide a survival benefit for metastatic chondrosarcoma, but not for osteosarcoma and Ewing sarcoma of pelvic bones, sacrum, and coccyx. This population-based study recommends an active surgical intervention for metastatic chondrosarcoma while non-surgical treatment for metastatic osteosarcoma and Ewing sarcoma of the pelvis in terms of survival improvement.

Serum lactate dehydrogenase as a novel prognostic factor for patients with primary undifferentiated pleomorphic sarcomas.

PURPOSE: Among soft tissue sarcomas, undifferentiated pleomorphic sarcoma (UPS) has relatively higher potential of recurrence and metastasis. As serum lactate dehydrogenase (LDH) is associated with tumor progression and unfavorable outcomes in multiple malignancies, we designed this study to explore the relationship between preoperative serum LDH and prognosis in UPS patients. METHODS: We extracted the data of UPS patients who underwent primary surgery in Shanghai Cancer Center, Fudan University. Receiver-operating characteristic (ROC) curve was used to figure out the best cutoff value of LDH to classify them into high- or low-expression groups. Univariate and multivariate analyses were performed using Cox proportional hazards regression to identify independent prognostic factors. Kaplan-Meier analysis was used to compare differences in overall survival (OS) and time to recurrence (TTR) between patients with high- or low-serum LDH. RESULTS: Multivariate analyses demonstrated that preoperative serum LDH was an independent factor for OS. Kaplan-Meier curves showed that patients with relatively high-serum LDH (P = 0.0004) had poorer OS compared with those with low-serum LDH. There was a trend that patients with relatively high-serum LDH had poorer TTR than those without (P = 0.1249). In addition, there were obvious trends that patients with decreased serum LDH after surgery showed better OS (P = 0.0954) and TTR (P = 0.1720) than those with elevated serum LDH. Moreover, high preoperative serum LDH was associated with female patients (P = 0.0004), positive margin (P < 0.0001), worse survival (P = 0.0061), higher mitotic index (P = 0.0222) and necrosis (P = 0.0225). CONCLUSIONS: Preoperative serum LDH is an independent factor for OS in UPS patients, and it correlates with future surgical margin.

From degenerative disease to malignant tumors: Insight to the function of ApoE.

Apolipoprotein E (ApoE) is a multifunctional protein involved in lipid transport and lipoprotein metabolism, mediating lipid distribution/redistribution in tissues and cells. It can also regulate inflammation and immune function, maintain cytoskeleton stability, and improve neural tissue Function. Due to genetic polymorphisms of ApoE (ε2, ε3, and ε4), its three common structural isoforms (ApoE2, ApoE3, ApoE4) are also associated with the risk of many diseases, especially degenerative diseases, such as vascular degenerative diseases including atherosclerosis (AS), coronary heart disease (CHD), and neurodegenerative disease like Alzheimer's disease (AD). The frequency of the ε4 allele and APOE variants were significantly higher than that of the ε2 and ε3 alleles in the patients with CHD or AD. In recent years, ApoE has frequently appeared in tumor research and become a tumor biomarker gradually. It has been found that ApoE is highly expressed in most solid tumor tissues, such as glioblastoma, gastric cancer, pancreatic ductal cell carcinoma, etc. Studies illustrated that ApoE could regulate the polarization changes of macrophages, participate in the construction of tumor immune microenvironment, regulate tumor inflammation and immune response and play a role in tumor progression, invasion, and metastasis. Of course, many functions of ApoE and its relationship with diseases are still under research. By reviewing the structure and function of ApoE from degeneration diseases to tumor neoplasms, we hope to better understand such a biomarker and further explore the value of ApoE in later studies.

Transcription factor c-Jun modulates GLUT1 in glycolysis and breast cancer metastasis.

As the main isoforms of membranous glucose transporters (GLUT), GLUT1 involves tumorigenesis, metastasis and prognosis in a variety of cancers. However, its role in breast cancer metastasis remains to be elucidated. Here we examined its transcriptional and survival data in patients with breast cancer from several independent databases including the Oncomine, Gene Expression Profiling Interactive Analysis, Gene Expression across Normal and Tumor tissue, UALCAN, cBioPortal, Kaplan-Meier Plotter and PROGgeneV2. We found that its mRNA expression was significantly high in cancer tissues, which was associated with metastasis and poor survival. Transcription factor c-Jun might bind to GLUT1 promoter to downregulate its gene expression or mRNA stability, therefore to suppress glycolysis and metastasis. By qRT-PCR, we verified that GLUT1 was significantly increased in 38 paired human breast cancer samples while JUN was decreased. Furthermore, the protein level of GLUT1 was higher in tumor than in normal tissues by IHC assay. To explore underlying pathways, we further performed GO and KEGG analysis of genes related to GLUT1 and JUN and found that GLUT1 was increased by transcription factor c-Jun in breast cancer tissues to influence glycolysis and breast cancer metastasis.

Artificial Intelligence in Dermatology Image Analysis: Current Developments and Future Trends.

BACKGROUND: Thanks to the rapid development of computer-based systems and deep-learning-based algorithms, artificial intelligence (AI) has long been integrated into the healthcare field. AI is also particularly helpful in image recognition, surgical assistance and basic research. Due to the unique nature of dermatology, AI-aided dermatological diagnosis based on image recognition has become a modern focus and future trend. Key scientific concepts of review: The use of 3D imaging systems allows clinicians to screen and label skin pigmented lesions and distributed disorders, which can provide an objective assessment and image documentation of lesion sites. Dermatoscopes combined with intelligent software help the dermatologist to easily correlate each close-up image with the corresponding marked lesion in the 3D body map. In addition, AI in the field of prosthetics can assist in the rehabilitation of patients and help to restore limb function after amputation in patients with skin tumors. THE AIM OF THE STUDY: For the benefit of patients, dermatologists have an obligation to explore the opportunities, risks and limitations of AI applications. This study focuses on the application of emerging AI in dermatology to aid clinical diagnosis and treatment, analyzes the current state of the field and summarizes its future trends and prospects so as to help dermatologists realize the impact of new technological innovations on traditional practices so that they can embrace and use AI-based medical approaches more quickly.

Langerhans Cell Histiocytosis: A Population-based Study of Anatomical Distribution and Treatment Patterns.

Background: Langerhans cell histiocytosis (LCH) is a rare monoclonal histiocytic neoplasm. Little is known about clinical factors associated with LCH single- vs multi-system involvement at the time of diagnosis. Methods: Data on 1549 LCH patients diagnosed between years 2010 and 2018 were extracted from the Surveillance, Epidemiology and End Results Program. Patterns of single- vs multisystem involvement were examined using multivariable logistic regression analysis. Odd ratio (OR) and 95% confidence interval (CI) were reported. Results: 968 children and adolescents (0-19 years; median: 4 years) and 581 adults (≥20 years; median: 49 years) were included in the analysis. Multi-system LCH was reported for 30.9 % patients. Bone marrow (BM) (OR = 3.776; 95 %CI = 1.939-7.351; P < 0.001) and lymph node (LN) (OR = 3.274; 95 %CI = 1.443-7.427; P = 0.005) involvement were most commonly associated with multi-system LCH at the time of diagnosis; similar pattern was also observed in adult patients (OR = 17.780; 95 %CI = 6.469-48.867; P < 0.001 for BM LCH; and OR = 5.156; 95 %CI = 2.131-12.471; P < 0.001 for LN LCH). Among pediatric patients, craniofacial osseous LCH was more likely to be treated with surgery (OR = 2.822; 95 %CI = 1.199-6.639; P = 0.018) compared to skeletal lesions in other sites, whereas vertebral body LCH was less likely to be treated with surgery (OR = 0.175; 95 %CI = 0.058-0.527; P = 0.002). In pediatric patients with bone LCH, the non-white patients were less likely to be treated surgically compared to the white patients (OR = 0.470; 95 %CI = 0.272-0.812; P = 0.007). Conclusions: BM and LN LCH are associated with the highest risks of multi-system disease, which may require active surveillance. Furthermore, active attempts are needed to mitigate the racial disparity in surgery utilization in pediatric patients with skeletal LCH.

Integrative analysis of synovial sarcoma transcriptome reveals different types of transcriptomic changes.

Background: Synovial sarcoma (SS) is a rare and aggressive cancer that can come from distinct soft tissue types including muscle and ligaments. However, the transcriptomic landscape of SS is still poorly understood. This study aimed to systematically dissect the changes in SS transcriptome from different perspectives. Methods: We performed deep total RNA sequencing on ten paired Synovial sarcoma and tumor-adjacent tissues to systematically dissect the transcriptomic profile of SS in terms of gene expression, alternative splicing, gene fusion, and circular RNAs. Results: A total of 2,309 upregulated and 1,977 downregulated genes were identified between SS and tumor-adjacent tissues. Those upregulated genes could lead to the upregulation of the cell cycle, ribosome, and DNA replication pathways, while the downregulated genes may result in the downregulation of a set of metabolic biological processes and signaling pathways. Moreover, 2,511 genes (including 21 splicing factors) were differentially alternative spliced, indicating that the deregulation of alternative splicing could be one important factor that contributes to tumorigenesis. Additionally, we identified the known gene fusions of SS18-SSX1/SSX2 as well as 11 potentially novel gene fusions. Interestingly, 49 circular RNAs were differentially expressed and their parental genes could function in muscle contraction and muscle system processes. Conclusions: Collectively, our comprehensive dissection of the transcriptomic changes of SS from both transcriptional and post-transcriptional levels provides novel insights into the biology and underlying molecular mechanism of SS.

Impact of racial disparities and insurance status in patients with bone sarcomas in the USA : a population-based cohort study.

AIMS: Socioeconomic and racial disparities have been recognized as impacting the care of patients with cancer, however there are a lack of data examining the impact of these disparities on patients with bone sarcoma. The purpose of this study was to examine socioeconomic and racial disparities that impact the oncological outcomes of patients with bone sarcoma. METHODS: We reviewed 4,739 patients diagnosed with primary bone sarcomas from the Surveillance, Epidemiology and End Results (SEER) registry between 2007 and 2015. We examined the impact of race and insurance status associated with the presence of metastatic disease at diagnosis, treatment outcome, and overall survival (OS). RESULTS: Patients with Medicaid (odds ratio (OR) 1.41; 95% confidence interval (CI) 1.15 to 1.72) and uninsured patients (OR 1.90; 95% CI 1.26 to 2.86) had higher risks of metastatic disease at diagnosis compared to patients with health insurance. Compared to White patients, Black (OR 0.63, 95% CI 0.47 to 0.85) and Asian/Pacific Islander (OR 0.65, 95% CI 0.46 to 0.91) were less likely to undergo surgery. In addition, Black patients were less likely to receive chemotherapy (OR 0.67, 95% CI 0.49 to 0.91) compared to White patients. In patients with chondrosarcoma, those with Medicaid had worse OS compared to patients with insurance (hazard ratio (HR) 1.65, 95% CI 1.06 to 2.56). CONCLUSION: In patients with a bone sarcoma, the cancer stage at diagnosis varied based on insurance status, and racial disparities were identified in treatment. Further studies are needed to identify modifiable factors which can mitigate socioeconomic and racial disparities found in patients with bone sarcomas. Cite this article: Bone Joint Res 2022;11(5):278-291.

Predictive factors, preventive implications, and personalized surgical strategies for bone metastasis from lung cancer: population-based approach with a comprehensive cancer center-based study.

Background: Bone metastasis (BM) and skeletal-related events (SREs) happen to advanced lung cancer (LC) patients without warning. LC-BM patients are often passive to BM diagnosis and surgical treatment. It is necessary to guide the diagnosis and treatment paradigm for LC-BM patients from reactive medicine toward predictive, preventive, and personalized medicine (PPPM) step by step. Methods: Two independent study cohorts including LC-BM patients were analyzed, including the Surveillance, Epidemiology, and End Results (SEER) cohort (n = 203942) and the prospective Fudan University Shanghai Cancer Center (FUSCC) cohort (n = 59). The epidemiological trends of BM in LC patients were depicted. Risk factors for BM were identified using a multivariable logistic regression model. An individualized nomogram was developed for BM risk stratification. Personalized surgical strategies and perioperative care were described for FUSCC cohort. Results: The BM incidence rate in LC patients grew (from 17.53% in 2010 to 19.05% in 2016). Liver metastasis was a significant risk factor for BM (OR = 4.53, 95% CI = 4.38-4.69) and poor prognosis (HR = 1.29, 95% CI = 1.25-1.32). The individualized nomogram exhibited good predictive performance for BM risk stratification (AUC = 0.784, 95%CI = 0.781-0.786). Younger patients, males, patients with high invasive LC, and patients with other distant site metastases should be prioritized for BM prevention. Spine is the most common site of BM, causing back pain (91.5%), pathological vertebral fracture (27.1%), and difficult walking (25.4%). Spinal surgery with personalized spinal reconstruction significantly relieved pain and improved daily activities. Perioperative inflammation, immune, and nutrition abnormities warrant personalized managements. Radiotherapy needs to be recommended for specific postoperative individuals. Conclusions: The presence of liver metastasis is a strong predictor of LC-BM. It is recommended to take proactive measures to prevent BM and its SREs, particularly in young patients, males, high invasive LC, and LC with liver metastasis. BM surgery and perioperative management are personalized and required. In addition, adjuvant radiation following separation surgery must also be included in PPPM-guided management. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-022-00270-9.

Circ-PTPDC1 promotes the Progression of Gastric Cancer through Sponging Mir-139-3p by Regulating ELK1 and Functions as a Prognostic Biomarker.

Circular RNAs (circRNAs) is a novel class of non-coding RNAs resulting from the non-canonical splicing of linear pre-mRNAs. However, the role of circRNAs in gastric cancer (GC) remains indistinct. This study aims to explore their potential modulation in GC and its prognostic value. We first screen for circRNA expression patterns in GC through GC and adjacent noncancerous tissues by microarray. Based on the bioinformatics analysis of the microarray data, we screened out a novel circRNA, circ-PTPDC1. Then we demonstrated that circ-PTPDC1 was up-regulated in GC cells, tissues, and serum. Its overexpression was positively correlated with age, invasion depth, advanced clinical stages, and worse survival in patients with GC. We further revealed that circ-PTPDC1 promotes the proliferation, migration, and invasion of GC cell lines via sponging miR-139-3p by regulating ELK1. Importantly, we identified that circ-PTPDC1 promotes tumor upgrowth and metabasis in vivo. Additionally, we established its prognostic prediction model based on the follow-up data of the patients. Our study revealed a novel regulatory mechanism and a comprehensive landscape of circ-PTPDC1 in GC, suggesting that circ-PTPDC1 has the potential to be a biomarker for early detection and prognostic prediction of GC.

Trends in Tumor Site-Specific Survival of Bone Sarcomas from 1980 to 2018: A Surveillance, Epidemiology and End Results-Based Study.

OBJECTIVES: As diagnosis and treatment guidelines for bone sarcomas continue updating, it is important to examine whether, when, and which kinds of patients have had a survival improvement over the last four decades. METHODS: This cohort study included 9178 patients with primary bone and joint sarcomas from 1 January 1980 to 31 December 2018 using data from Surveillance, Epidemiology and End Results (SEER)-9 Registries. The follow-up period was extended to November 2020. Patients were divided by decade into four time periods: 1980-1989, 1990-1999, 2000-2009, and 2010-2018. The primary endpoint was bone sarcomas-specific mortality (CSM). The 5-year bone sarcomas-specific survival (CSS) rate was determined stratified by demographic, neoplastic, temporal, economic, and geographic categories. The associations between time periods and CSM were examined using a multivariable Cox regression model, with reported hazard ratio (HR) and 95% confidence interval (CI). RESULTS: The 5-year CSS rate for bone sarcomas was 58.7%, 69.9%, 71.0%, and 69.2%, in the 1980s, 1990s, 2000s, and 2010s, respectively. Older age, male gender, tumor sites at pelvic bones, sacrum, coccyx and associated joints, as well as vertebral column, osteosarcoma and Ewing tumor, and residence in non-metropolitan areas were independently associated with higher CSM risk. After adjusting for the covariates above, patients in the 1990s (HR = 0.74, 95% CI = 0.68-0.82), 2000s (HR = 0.71, 95% CI = 0.65-0.78), and 2010s (HR = 0.68, 95% CI = 0.62-0.76) had significantly lower CSM risks than patients in the 1980s. However, patients in the 2000s and 2010s did not have lower CSM risks than those in the 1990s (both p > 0.05). CONCLUSIONS: Although bone sarcomas survival has significantly improved since 1990, it almost halted over the next three decades. Bone sarcomas survival should improve over time, similar to common cancers. New diagnostic and therapeutic strategies such as emerging immune and targeted agents are warranted to overcome this survival stalemate.