Osteosarcoma Patients Research Articles

Efficacy of Recombinant Human Endostatin plus Neoadjuvant Chemotherapy for Osteosarcoma and Its Influence on Serum VEGF and MMP-9 Levels.

To investigate the efficacy of recombinant human endostatin (rh-Endo) plus neoadjuvant chemotherapy (NACT) for osteosarcoma (OSA) and its influence on serum vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9). The case data of 141 OSA patients presented to the North District, Xiangyang Central Hospital Affiliated to Hubei University of Arts and Sciences from January 2018 to June 2019, were analyzed retrospectively. Patients receiving NACT (methotrexate + ifosfamide + adriamycin) were assigned into the control group (CNG; n = 65), while those treated with rh-Endo plus NACT were included in the combination group (CMG; n = 76). The following aspects were compared: clinical efficacy, serum tumor markers, serum VEGF and MMP-9 contents, inflammatory factors, incidence of adverse reactions, limb function scores at 6 months of follow-up, and prognostic quality of life (QOL). A statistically higher overall response rate (ORR) was determined in CMG versus CNG (84.2% vs. 64.6%, P < 0.05). The pretreatment serum bone alkaline phosphatase (BALP), insulin-like growth factor (IGF)-1, serum amyloid A (SAA), VEGF, MMP-9, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, and interleukin (IL)-10 levels differed insignificantly between the two cohorts (P > 0.05); while except IL-10 that showed increased expression in both cohorts and was comparatively higher in CMG, the other 8 parameters reduced in both cohorts after 2 weeks of drug withdrawal, and the reduction of each parameter was more significant in CMG (P < 0.05). The total adverse reaction rate was 30.2% in CMG, which was higher than that of 36.9% in CNG, albeit without a statistical difference (P > 0.05). An evidently higher 2-year survival rate was determined in CMG (P < 0.05). rh-Endo plus NACT is more effective than NACT alone in the treatment of osteosarcoma, which can validly restore the balance of vascular endothelial cells, reduce inflammation, and is worth promoting in clinic.

Osteosarcomas in older adults: A report from the Cooperative Osteosarcoma Study Group

IntroductionOsteosarcoma is typically a disease of the young, but may affect any age. Little is known about the disease in older patients beyond retirement age. We aim to describe the characteristics, treatment, and outcomes of older adult patients registered with our cooperative group. Materials and MethodsThe database of the Cooperative Osteosarcoma Study Group (COSS) was searched for osteosarcoma patients diagnosed from 1980 to 2020 who were aged 65 years or older at diagnosis. Affected individuals were analyzed for presenting factors, treatments employed, and outcomes. ResultsFifty-five eligible patients were detected (median age 68 [range: 65–84] years; male:female = 25:30). Among these patients, 15/55 (27%) tumors were secondary malignancies, 41/55 (75%) were high-grade central, 4/55 (7%) surface, and 10/55 (18%) extraosseous malignancies, and all but three high-grade. Primary metastases were present in 15/55 (27%) patients. Surgery was reported for 46/55 (84%) patients, radiotherapy for 6/54 (11%, 1 unknown), chemotherapy for 42/50 (84%, 5 unknown). A complete surgical remission was achieved in 31/55 (56%). There were two toxic deaths. With a median follow-up of 1.7 (range: 0.1–18.0) years for all 55 patients and 2.2 (0.1–12.4) years for 24 survivors, event-free and overall survival at 2/5 years were 39.6% (standard error: 6.8%) / 24.5% (6.5%) and 62.0% (7.1%) / 32.7% (7.5%), respectively. Tumor site, metastatic status, surgery, and a complete surgical remission were prognostic for event-free and/or overall survival. DiscussionOsteosarcomas can occur in older individuals. It is more often secondary, axially located, or extraosseous than in younger patients. However, the same treatment principles seem to apply, and selected patients may be cured. Multi-center cooperation is encouraged, thereby gathering expertise for such a rare disease presentation.

Indirect bilirubin impairs invasion of osteosarcoma cells via inhibiting the PI3K/AKT/MMP-2 signaling pathway by suppressing intracellular ROS

BackgroundOsteosarcoma is most prevalently found primary malignant bone tumors, with primary metastatic patients accounting for approximately 25% of all osteosarcoma patients, yet their 5-year OS remains below 30%. Bilirubin plays a key role in oxidative stress-associated events, including malignancies, making the regulation of its serum levels a potential anti-tumor strategy. Herein, we investigated the association of osteosarcoma prognosis with serum levels of TBIL, IBIL and DBIL, and further explored the mechanisms by which bilirubin affects tumor invasion and migration. MethodsROC curve was plotted to assess survival conditions based on the determined optimal cut-off values and the AUC. Then, Kaplan-Meier curves, along with Cox proportional hazards model, was applied for survival analysis. Inhibitory function of IBIL on the malignant properties of osteosarcoma cells was examined using the qRT-PCR, transwell assays, western blotting, and flow cytometry. ResultsWe found that, versus osteosarcoma patients with pre-operative higher IBIL (>8.9 μmol/L), those with low IBIL (≤8.9 μmol/L) had shorter OS and PFS. As indicated by the Cox proportional hazards model, pre-operative IBIL functioned as an independent prognostic factor for OS and PFS in total and gender-stratified osteosarcoma patients (P < 0.05 for all). In vitro experiments further confirmed that IBIL inhibits PI3K/AKT phosphorylation and downregulates MMP-2 expression via reducing intracellular ROS, thereby decreasing the invasion of osteosarcoma cells. ConclusionsIBIL may serve as an independent prognostic predictor for osteosarcoma patients. IBIL impairs invasion of osteosarcoma cells through repressing the PI3K/AKT/MMP-2 pathway by suppressing intracellular ROS, thus inhibiting its metastatic potential.

Association of circulating tumor cells and IMP3 expression with metastasis of osteosarcoma.

Circulating tumor cells (CTCs) have been identified as a prognostic biomarker of tumors such as breast cancer and nasopharyngeal carcinoma, because they are obtained through a simple and noninvasive blood draw or liquid biopsy, but its clinical significance in osteosarcoma is still unclear. In this study, we analyzed the relationship between CTCs and clinicopathological features and discussed whether CTCs could be used as a biomarker for metastasis in osteosarcoma. We enrolled 50 osteosarcoma patients with Enneking Stage IIB and Stage III and detected CTCs in 5ml of peripheral blood samples collected from patients using the Canpatrol® CTC detection platform. Subsequently, multiplex RNA in situ hybridization (RNA-ISH) based on various molecular markers was performed to identify and classify CTCs. The relationships between clinical pathological features and CTC counts, subtypes (epithelial type, E type; hybrid epithelial/mesenchymal type, H type; mesenchymal type, M type), and insulin-like growth factor mRNA-binding protein 3 (IMP3) expression in CTCs were analyzed. CTCs were detected in 86% (43/50) of the osteosarcoma patients. The CTC counts, especially the total CTCs and H-type CTCs, signifcantly differed between Enneking Stage IIB and Stage III patients (P < 0.05). No significant differences were observed between the CTC count or type and other clinicopathological features (P > 0.05). There were significant differences in the expression of IMP3 in different types of CTCs, and the IMP3 positive rates in E/H/M type CTCs were 38.4, 65.6, and 62.0%, respectively (P < 0.001). Receiver operating characteristic (ROC) curve analysis showed that IMP3-positive CTC count had the best performance for diagnostic metastasis, with the largest area under the curve of 0.873 and cutoff value of four cells/5ml blood (sensitivity = 87.5%; specificity = 82.4%). Serial CTC monitoring in one patient suggested that total CTCs and H-type CTCs were associated with disease progression. This study demonstrates that the CTCs, especially the IMP3-positive CTCs and H/M-type CTCs, are related to the metastasis of osteosarcoma.

GINS2 Promotes Osteosarcoma Tumorigenesis via STAT3/MYC Axis.

GINS2 is overexpressed in several cancers, but little is known about its role in osteosarcoma (OS). A series of in vivo and in vitro experiments were conducted to explore the role of GINS2 in OS. In this study, we demonstrated that GINS2 was found to be highly expressed in OS tissues and cell lines, which was associated with poor outcomes in OS patients. GINS2 knockdown hindered the growth and induced apoptosis in OS cell lines in vitro. Furthermore, GINS2 knockdown effectively inhibited the growth of a xenograft tumor in vivo. By using an Affymetrix gene chip and intelligent pathway analysis, it was demonstrated that the GINS2 knockdown could reduce the expression of several targeted genes and reduce the activity of the MYC signaling pathway. Mechanically, LC-MS, CoIP, and rescue experiments revealed that GINS2 promoted tumor progression through the STAT3/MYC axis in the OS. Moreover, GINS2 was associated with tumor immunity and may be a potential immunotherapeutic target for OS.

Identification and verification of a BMPs-related gene signature for osteosarcoma prognosis prediction

BackgroundThis study aimed to get a deeper insight into new osteosarcoma (OS) signature based on bone morphogenetic proteins (BMPs)-related genes and to confirm the prognostic pattern to speculate on the overall survival among OS patients.MethodsFirstly, pathway analyses using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were managed to search for possible prognostic mechanisms attached to the OS-specific differentially expressed BMPs-related genes (DEBRGs). Secondly, univariate and multivariate Cox analysis was executed to filter the prognostic DEBRGs and establish the polygenic model for risk prediction in OS patients with the least absolute shrinkage and selection operator (LASSO) regression analysis. The receiver operating characteristic (ROC) curve weighed the model’s accuracy. Thirdly, the GEO database (GSE21257) was operated for independent validation. The nomogram was initiated using multivariable Cox regression. Immune infiltration of the OS sample was calculated. Finally, the three discovered hallmark genes’ mRNA and protein expressions were verified.ResultsA total of 46 DEBRGs were found in the OS and control samples, and three prognostic DEBRGs (DLX2, TERT, and EVX1) were screened under the LASSO regression analyses. Multivariate and univariate Cox regression analysis were devised to forge the OS risk model. Both the TARGET training and validation sets indicated that the prognostic biomarker-based risk score model performed well based on ROC curves. In high- and low-risk groups, immune cells, including memory B, activated mast, resting mast, plasma, and activated memory CD4 + T cells, and the immune, stromal, and ESTIMATE scores showed significant differences. The nomogram that predicts survival was established with good performance according to clinical features of OS patients and risk scores. Finally, the expression of three crucial BMP-related genes in OS cell lines was investigated using quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB).ConclusionThe new BMP-related prognostic signature linked to OS can be a new tool to identify biomarkers to detect the disease early and a potential candidate to better treat OS in the future.

Contribution of Mitochondrial Activity to Doxorubicin-Resistance in Osteosarcoma Cells

Osteosarcoma is considered the most common bone tumor affecting children and young adults. The standard of care is chemotherapy; however, the onset of drug resistance still jeopardizes osteosarcoma patients, thus making it necessary to conduct a thorough investigation of the possible mechanisms behind this phenomenon. In the last decades, metabolic rewiring of cancer cells has been proposed as a cause of chemotherapy resistance. Our aim was to compare the mitochondrial phenotype of sensitive osteosarcoma cells (HOS and MG-63) versus their clones when continuously exposed to doxorubicin (resistant cells) and identify alterations exploitable for pharmacological approaches to overcome chemotherapy resistance. Compared with sensitive cells, doxorubicin-resistant clones showed sustained viability with less oxygen-dependent metabolisms, and significantly reduced mitochondrial membrane potential, mitochondrial mass, and ROS production. In addition, we found reduced expression of TFAM gene generally associated with mitochondrial biogenesis. Finally, combined treatment of resistant osteosarcoma cells with doxorubicin and quercetin, a known inducer of mitochondrial biogenesis, re-sensitizes the doxorubicin effect in resistant cells. Despite further investigations being needed, these results pave the way for the use of mitochondrial inducers as a promising strategy to re-sensitize doxorubicin cytotoxicity in patients who do not respond to therapy or reduce doxorubicin side effects.

Metastasis-Related Signature for Clinically Predicting Prognosis and Tumor Immune Microenvironment of Osteosarcoma Patients

Osteosarcoma is the most prevalent clinical malignant bone tumor in adolescents. The prognosis of metastatic osteosarcoma is still very poor. The aim of our study was to investigate the clinical diagnosis and prognostic significance of metastasis related genes (MRGs) in patients with osteosarcoma. Clinical information and RNA sequencing data with osteosarcoma patients were obtained and set as the training set from UCSC databases. GSE21257 were downloaded and chosen as the verification cohort. An eight gene metastasis related risk signature including MYC, TAC4, ABCA4, GADD45GIP1, TNFRSF21, HERC5, MAGEA11, and PDE1B was built to predict the overall survival of osteosarcoma patients. Based on risk assessments, patients were classified into high- and low-risk groups. The high-risk patients had higher risk score and shorter survival time. ROC curves revealed that this risk signature can accurately predict survival times of osteosarcoma patients at the 1-, 2-, 3-, 4- and 5- year. GSEA revealed that MYC targets, E2F targets, mTORC1 signaling, Wnt /β-catenin signaling and cell cycle were upregulated, and cell adhesion molecules, and primary immunodeficiency were decreased in high-risk group. MRGs were highly linked with the tumor immune microenvironment and ICB response. These results identified that MRGs as a novel prognostic and diagnostic biomarker in osteosarcoma.

TREM2 as a Prognostic Biomarker for Osteosarcoma Microenvironment Remodeling.

The tumor microenvironment (TME) acts as a crucial role in the occurrence and development of osteosarcoma (OS). Despite this, the mechanism controlling the components of immunity and stroma in the tumor microenvironment remains a mystery. To conduct this study, we download and collate transcriptome data from the TARGET database, whose full name is Therapeutically Applicable Research to Generate Effective Treatments, as well as available clinical information of OS. The CIBERSORT and ESTIMATE methodology are used to acquire the proportions of components of immunity and stroma and tumor-infiltrating immune cells (TICs). Protein-protein interaction (PPI) networks and Cox regression analysis are used to select differentially expressed genes (DEGs). A prognostic biomarker is determined by intersecting univariate COX and PPI results, which lead to the finding of Triggering receptor expressed on myeloid cells-2 (TREM2). Based on the next analysis, TREM2 expression is positively correlated with OS survival time. Immune function-related genes have enrichment in the group with high expression of TREM2, according to gene set enrichment analysis (GSEA). The percentage of TICs by CIBERSORT methodology revealed that the expression of TREM2 is positively associated with follicular helper T cells, CD8-positive T cells, and M2 macrophages and negatively correlated with plasma cells, M0 macrophages, and naive CD4-positive T cells. All results suggest a possible integral role of TREM2 in the immune-related events of TME. Therefore, TREM2 may be a potential indicator of remodeling of TME in osteosarcoma, which is useful and helpful in predicting the clinical prognostic outcome of OS patients and provide a unique perspective for immunotherapy for OS.

Molecular features and predictive models identify the most lethal subtype and a therapeutic target for osteosarcoma.

Osteosarcoma is the most common primary malignant bone tumor. The existing treatment regimens remained essentially unchanged over the past 30 years; hence the prognosis has plateaued at a poor level. Precise and personalized therapy is yet to be exploited. One discovery cohort (n=98) and two validation cohorts (n=53 & n=48) were collected from public data sources. We performed a non-negative matrix factorization (NMF) method on the discovery cohort to stratify osteosarcoma. Survival analysis and transcriptomic profiling characterized each subtype. Then, a drug target was screened based on subtypes' features and hazard ratios. We also used specific siRNAs and added a cholesterol pathway inhibitor to osteosarcoma cell lines (U2OS and Saos-2) to verify the target. Moreover, PermFIT and ProMS, two support vector machine (SVM) tools, and the least absolute shrinkage and selection operator (LASSO) method, were employed to establish predictive models. We herein divided osteosarcoma patients into four subtypes (S-I ~ S-IV). Patients of S- I were found probable to live longer. S-II was characterized by the highest immune infiltration. Cancer cells proliferated most in S-III. Notably, S-IV held the most unfavorable outcome and active cholesterol metabolism. SQLE, a rate-limiting enzyme for cholesterol biosynthesis, was identified as a potential drug target for S-IV patients. This finding was further validated in two external independent osteosarcoma cohorts. The function of SQLE to promote proliferation and migration was confirmed by cell phenotypic assays after the specific gene knockdown or addition of terbinafine, an inhibitor of SQLE. We further employed two machine learning tools based on SVM algorithms to develop a subtype diagnostic model and used the LASSO method to establish a 4-gene model for predicting prognosis. These two models were also verified in a validation cohort. The molecular classification enhanced our understanding of osteosarcoma; the novel predicting models served as robust prognostic biomarkers; the therapeutic target SQLE opened a new way for treatment. Our results served as valuable hints for future biological studies and clinical trials of osteosarcoma.

NSUN2 promotes osteosarcoma progression by enhancing the stability of FABP5 mRNA via m5C methylation

5-methylcytosine (m5C) modification, which is mainly induced by the RNA methyltransferase NSUN2 (NOP2/Sun domain family, member 2), is an important chemical posttranscriptional modification in mRNA and has been proven to play important roles in the progression of many cancers. However, the functions and underlying molecular mechanisms of NSUN2-mediated m5C in osteosarcoma (OS) remain unclear. In this study, we found NSUN2 was highly expressed in OS tissues and cells. We also discovered that higher expression of NSUN2 predicted poorer prognosis of OS patients. Our study showed that NSUN2 could promote the progression of OS cells. Moreover, we employed RNA sequencing, RNA immunoprecipitation (RIP), and methylated RIP to screen and validate the candidate targets of NSUN2 and identified FABP5 as the target. We observed that NSUN2 stabilized FABP5 mRNA by inducing m5C modification and further promoted fatty acid metabolism in OS cells. Moreover, both knocking down the expression of FABP5 and adding fatty acid oxidation inhibitor could counterbalance the promoting effect of NSUN2 on the progression of OS. Our study confirms that NSUN2 can up-regulate the expression of FABP5 by improving the stability of FABP5 mRNA via m5C, so as to promote fatty acid metabolism in OS cells, and finally plays the role in promoting the progression of OS. Our findings suggest that NSUN2 is a promising prognostic marker for OS patients and may serve as a potential therapeutic target for OS treatment.A schematic illustration was proposed to summarize our findings.

ITGB3 promotes cisplatin resistance in osteosarcoma tumors.

Osteosarcoma is the most malignant and common primary bone tumor with a high rate of recurrence that mainly occurs in children and young adults. Therefore, it is vital to facilitate the development of novel effective therapeutic means and improve the overall prognosis of osteosarcoma patients via a deeper understanding of the mechanisms of chemoresistance in osteosarcoma progression. In this research, the relationship between ITGB3 and the clinical characteristics of patients was detected through analysis of publicly available clinical datasets. The expression of ITGB3 was analysis in collected human osteosarcoma tissues. In addition, the potential functions of ITGB3 in the cisplatin resistance of osteosarcoma cells were investigated in vitro and in tumor xenotransplantation. Finally, the molecular mechanism of ITGB3 in the progression and recurrence of osteosarcoma were explored via transcriptome analysis. ITGB3 was identified as a potential regulator of tumorigenicity and cisplatin resistance in relapsed osteosarcoma. Furthermore, the decreased osteosarcoma cell proliferation and migration ability in ITGB3 knockout osteosarcoma cells were related to increased apoptosis and slowing cell cycle progression. In addition, ITGB3 had a positive correlation with cisplatin resistance in cells and tumor xenografts in mice. Accordingly, ITGB3 performed the functions of proliferation and cisplatin resistance in osteosarcoma through the MAPK and VEGF signaling pathways. Our results will contribute to a better understanding of the function and mechanism of ITGB3 in osteosarcoma cisplatin resistance and provide a novel therapeutic target to decrease cisplatin resistance and tumor recurrence in osteosarcoma patients.

A clinical prediction model for lung metastasis risk in osteosarcoma: A multicenter retrospective study.

Lung metastases (LM) have a poor prognosis of osteosarcoma. This study aimed to predict the risk of LM using the nomogram in patients with osteosarcoma. A total of 1100 patients who were diagnosed as osteosarcoma between 2010 and 2019 in the Surveillance, Epidemiology and End Results (SEER) database were selected as the training cohort. Univariate and multivariate logistic regression analyses were used to identify independent prognostic factors of osteosarcoma lung metastases. 108 osteosarcoma patients from a multicentre dataset was as valiation data. The predictive power of the nomogram model was assessed by receiver operating characteristic curves (ROC) and calibration plots, and decision curve analysis (DCA) was utilized to interpret the accurate validity in clinical practice. A total of 1208 patients with osteosarcoma from both the SEER database(n=1100) and the multicentre database (n=108) were analyzed. Univariate and multivariate logistic regression analyses showed that Survival time, Sex, T-stage, N-stage, Surgery, Radiation, and Bone metastases were independent risk factors for lung metastasis. We combined these factors to construct a nomogram for estimating the risk of lung metastasis. Internal and external validation showed significant predictive differences (AUC 0.779, 0.792 respectively). Calibration plots showed good performance of the nomogram model. In this study, a nomogram model for predicting the risk of lung metastases in osteosarcoma patients was constructed and turned out to be accurate and reliable through internal and external validation. Moreover we built a webpage calculator (https://drliwenle.shinyapps.io/OSLM/) taken into account nomogram model to help clinicians make more accurate and personalized predictions.

The Prognostic Model Established by the Differential Expression Genes Based on CD8+ T Cells to Evaluate the Prognosis and the Response to Immunotherapy in Osteosarcoma.

Osteosarcoma (OS) is a malignant tumor with an extremely poor prognosis, especially in progressive patients. Immunotherapy based on immune checkpoint inhibitors (ICIs) is considered to be a promising treatment option for OS. Due to tumor heterogeneity, only a minority of patients benefit from immunotherapy. Therefore, it is urgent to explore a model that can accurately assess the response of OS to immunotherapy. In this study, we obtained the single-cell RNA sequencing datasets of OS patients from public databases and defined 34 cell clusters by dimensional reduction and clustering analysis. PTPRC was applied to identify immune cell clusters and nonimmune cell clusters. Next, we performed clustering analysis on the immune cell clusters and obtained 25 immune cell subclusters. Immune cells were labeled with CD8A and CD8B to obtain CD8+ T cell clusters. Meanwhile, we extracted the differentially expressed genes (DEGs) of CD8+ T cell clusters and other immune cell clusters. Furthermore, we constructed a prognostic model (CD8-DEG model) based on the obtained DEGs of CD8+ T cells, and verified the excellent predictive ability of this model for the prognosis of OS. Moreover, we further investigated the value of the CD8-DEG model. The results indicated that the risk score of the CD8-DEG model was an independent risk factor for OS patients. Finally, we revealed that the risk score of the CD8-DEG model correlates with the immune profile of OS and can be used to evaluate the response of OS to immunotherapy. In conclusion, our study revealed the critical role of CD8 cells in OS. The risk score model based on CD8-DEGs can provide guidance for prognosis and immunotherapy of OS.

Single-cell RNA datasets and bulk RNA datasets analysis demonstrated C1Q+ tumor-associated macrophage as a major and antitumor immune cell population in osteosarcoma.

Osteosarcoma is the most frequent primary bone tumor with a poor prognosis. Immune infiltration proved to have a strong impact on prognosis. We analyzed single-cell datasets and bulk datasets to confirm the main immune cell populations and their properties in osteosarcoma. The examples in bulk datasets GSE21257 and GSE32981 from the Gene Expression Omnibus database were divided into two immune infiltration level groups, and 34 differentially expressed genes were spotted. Then, we located these genes among nine major cell clusters and their subclusters identified from 99,668 individual cells in single-cell dataset GSE152048 including 11 osteosarcoma patients. Especially, the markers of all kinds of myeloid cells identified in single-cell dataset GSE152048 were set to gene ontology enrichment. We clustered the osteosarcoma samples in the TARGET-OS from the Therapeutically Applicable Research to Generate Effective Treatments dataset into two groups by complete component 1q positive macrophage markers and compared their survival. Compared with the low-immune infiltrated group, the high-immune infiltrated group showed a better prognosis. Almost all the 34 differentially expressed genes expressed higher or exclusively among myeloid cells. A group of complete component 1q-positive macrophages was identified from the myeloid cells. In the bulk dataset TARGET-OS, these markers and the infiltration of complete component 1q-positive macrophages related to longer survival. Complete component 1q-positive tumor-associated macrophages were the major immune cell population in osteosarcoma, which contributed to a better prognosis.

Impact of Age at Diagnosis onCardiotoxicity in High-Grade Osteosarcoma and Ewing SarcomaPatients.

Osteosarcoma and Ewing sarcoma patients face a significant risk of cardiotoxicity as defined by left ventricular dysfunction and heart failure (HF). This study sought to evaluate the association between age at sarcoma diagnosis and incident HF. A retrospective cohort study was performed at the largest sarcoma center in the Netherlands among patients with an osteosarcoma or Ewing sarcoma. All patients were diagnosed and treated over a 36-year period(1982-2018) and followed until August 2021. Incident HF was adjudicated through the universal definition of heart failure. Determinants including age at diagnosis, doxorubicin dose, and cardiovascular risk factors wereentered as fixed or time-dependent covariates into a cause-specific Cox model to assess their impact on incident HF. The study population consisted of 528 patients with a median age at diagnosis of 19 years (Q1-Q3: 15-30 years). Over a median follow-up time of 13.2 years (Q1-Q3: 12.5-14.9 years), 18 patients developed HF with an estimated cumulative incidence of 5.9% (95% CI: 2.8%-9.1%). In a multivariable model, age at diagnosis (HR: 1.23; 95% CI: 1.06-1.43) per 5-year increase, doxorubicin dose per 10-mg/m2 increase (HR: 1.13; 95% CI: 1.03-1.24), and female sex (HR: 3.17; 95% CI: 1.11-9.10) were associated with HF. In a large cohort of sarcoma patients, we found that patients diagnosed at an older age are more prone to develop HF.

MUC1 promotes cancer stemness and predicts poor prognosis in osteosarcoma.

Osteosarcoma (OS) is one of the most common primary bone malignancy. Combining chemotherapy and surgical treatment significantly improved clinical outcomes for osteosarcoma patients. Osteosarcoma stem cells (OSCs) are often more malignant than differentiated cancer cells and are a key determinant of responses to chemotherapy and radiation therapy, therefore, the removal of OSCs could be an effective therapeutic strategy. Myxoprotein 1 (MUC1) is aberrantly overexpressed in many human cancers and it promotes cancer stemness through activation of pluripotency networks. In this study, we observed elevated MUC1 in osteosarcoma and a depressed prognosis in patients with high MUC1 expression profiles. Our observations also revealed that MUC1 promoted OS stemness and tumor metastasis both in vivo and in vitro. These data led us to hypothesize that MUC1 may be a therapeutic target for patients with OS.

Real-World Data on Cabozantinib in Advanced Osteosarcoma and Ewing Sarcoma Patients: A Study from the Hellenic Group of Sarcoma and Rare Cancers.

Advanced osteosarcomas (OSs) and Ewing sarcomas (ESs) tend to have poor prognosis with limited therapeutic options beyond first-line therapy. Aberrant angiogenesis and MET signaling play an important role in preclinical models. The anti-angiogenic drug cabozantinib was tested in a phase 2 trial of advanced OS and ES and was associated with clinical benefits. We retrospectively analyzed the off-label use of cabozantinib in adult patients with advanced OS and ES/primitive neuroectodermal tumors (PNETs) in three centers of the Hellenic Group of Sarcoma and Rare Cancers (HGSRC). Between April 2019 and January 2022, 16 patients started taking 60 mg of cabozantinib for advanced bone sarcoma or PNET. Median age at cabozantinib initiation was 31 years (17-83). All patients had received peri-operative chemotherapy for primary sarcoma and between 0 and 4 lines of treatment (median; 2.5) for advanced disease. The most common adverse effects included fatigue, anorexia, hypertransaminasemia, weight loss, and diarrhea. One toxic death was noted (cerebral hemorrhage). Dose reduction to 40 mg was required in 31.3% of the patients. No objective response was noted, and 9/16 patients exhibited stable disease outcomes. Progression-free survival varied from 1 to 8 (median; 5) months. Our study demonstrates that cabozantinib has antitumor activity in this population. In the real-life setting, we observed similar adverse events as in the CABONE study and in other neoplasms.

2-Hydroxy-3-methylanthraquinone inhibits homologous recombination repair in osteosarcoma through the MYC-CHK1-RAD51 axis

BackgroundOsteosarcoma is a malignant bone tumor that usually affects adolescents aged 15–19 y. The DNA damage response (DDR) is significantly enhanced in osteosarcoma, impairing the effect of systemic chemotherapy. Targeting the DDR process was considered a feasible strategy benefitting osteosarcoma patients. However, the clinical application of DDR inhibitors is not impressive because of their side effects. Chinese herbal medicines with high anti-tumor effects and low toxicity in the human body have gradually gained attention. 2-Hydroxy-3-methylanthraquinone (HMA), a Chinese medicine monomer found in the extract of Oldenlandia diffusa, exerts significant inhibitory effects on various tumors. However, its anti-osteosarcoma effects and defined molecular mechanisms have not been reported.MethodsAfter HMA treatment, the proliferation and metastasis capacity of osteosarcoma cells was detected by CCK-8, colony formation, transwell assays and Annexin V-fluorescein isothiocyanate/propidium iodide staining. RNA-sequence, plasmid infection, RNA interference, Western blotting and immunofluorescence assay were used to investigate the molecular mechanism and effects of HMA inhibiting osteosarcoma. Rescue assay and CHIP assay was used to further verified the relationship between MYC, CHK1 and RAD51.ResultsHMA regulate MYC to inhibit osteosarcoma proliferation and DNA damage repair through PI3K/AKT signaling pathway. The results of RNA-seq, IHC, Western boltting etc. showed relationship between MYC, CHK1 and RAD51. Rescue assay and CHIP assay further verified HMA can impair homologous recombination repair through the MYC-CHK1-RAD51 pathway.ConclusionHMA significantly inhibits osteosarcoma proliferation and homologous recombination repair through the MYC-CHK1-RAD51 pathway, which is mediated by the PI3K-AKT signaling pathway. This study investigated the exact mechanism of the anti-osteosarcoma effect of HMA and provided a potential feasible strategy for the clinical treatment of human osteosarcoma.Graphical

Lung and bone metastases patterns in osteosarcoma: Chemotherapy improves overall survival.

Osteosarcoma (OS) is a malignant tumor originating from the mesenchymal tissue. Simultaneous reports of lung and bone metastases (BM) in OS are rare in the literature. A total of 353 new cases of lung metastases (LM), 93 new cases of BM, and 59 new cases of LM and BM were diagnosed in the Surveillance, Epidemiology and End Results (SEER) database from 2010 to 2019. Univariate and multivariate logistic regression analyses were used to identify risk factors for LM and/or BM, and Cox regression analyses were performed to identify the prognostic factors for LM and/or BM. Kaplan-Meier (K-M) curves and log-rank tests were used to analyze the overall survival of patients with LM and/or BM. LM was diagnosed in 353 patients. Female sex, tumor size >100 mm, telangiectatic OS type, central OS type, N1 stage, other locations, BM, surgical treatments, radiotherapy and chemotherapy were significantly correlated with LM. 93 patients were diagnosed with BM. 25 to 59 years old, T1 stage, presence of LM, liver metastases, radiotherapy, and surgical treatments were significantly correlated with the BM. 59 patients were diagnosed with LM and BM. The chondroblastic OS type, small cell OS type, T1 stage, N1 stage, other locations, liver metastases, radiotherapy, and surgical treatments were significantly correlated with LM and BM. Metastases, radiotherapy, and surgery at the primary site were significantly associated with LM and/or BM. Chemotherapy at the primary site has been shown to be effective in improving the survival rate of LM and/or BM. Of the OS patients with LM, 61.47% died, and older age, BM, no surgery, and no chemotherapy were harmful to survival. 72.04% of OS patients with BM died, and N1 stage, no surgery, and no chemotherapy were harmful for survival. 69.49% of OS patients with LM and BM died, and older age and no chemotherapy were harmful for survival.