Bioactive nanocomposite hydrogel enhances postoperative immunotherapy and bone reconstruction for osteosarcoma treatment.

Osteosarcoma, a malignant bone tumor often characterized by high hedgehog signaling activity, residual tumor cells, and substantial bone defects, poses significant challenges to both treatment response and postsurgical recovery. Here, we developed a nanocomposite hydrogel for the sustained co-delivery of bioactive magnesium ions, anti-PD-L1 antibody (αPD-L1), and hedgehog pathway antagonist vismodegib, to eradicate residual tumor cells while promoting bone regeneration post-surgery. In a mouse model of tibia osteosarcoma, this hydrogel-mediated combination therapy led to remarkable tumor growth inhibition and hence increased animal survival by enhancing the activity of tumor-suppressed CD8+ T cells. Meanwhile, the implanted hydrogel improved the microenvironment of osteogenesis through long-term sustained release of Mg2+, facilitating bone defect repair by upregulating the expression of osteogenic genes. After 21 days, the expression levels of ALP, COL1, RUNX2, and BGLAP in the Vis-αPD-L1-Gel group were approximately 4.1, 5.1, 5.5, and 3.4 times higher than those of the control, respectively. We believe that this hydrogel-based combination therapy offers a potentially valuable strategy for treating osteosarcoma and addressing the tumor-related complex bone diseases.

Develop a Novel Signature to Predict the Survival and Affect the Immune Microenvironment of Osteosarcoma Patients: Anoikis-Related Genes.

Objective: Osteosarcoma (OS) represents a prevalent primary bone neoplasm predominantly affecting the pediatric and adolescent populations, presenting a considerable challenge to human health. The objective of this investigation is to develop a prognostic model centered on anoikis-related genes (ARGs), with the aim of accurately forecasting the survival outcomes of individuals diagnosed with OS and offering insights into modulating the immune microenvironment. Methods: The study's training cohort comprised 86 OS patients sourced from The Cancer Genome Atlas database, while the validation cohort consisted of 53 OS patients extracted from the Gene Expression Omnibus database. Differential analysis utilized the GSE33382 dataset, encompassing three normal samples and 84 OS samples. Subsequently, the study executed gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses. Identification of differentially expressed ARGs associated with OS prognosis was carried out through univariate COX regression analysis, followed by LASSO regression analysis to mitigate overfitting risks and construct a robust prognostic model. Model accuracy was assessed via risk curves, survival curves, receiver operating characteristic curves, independent prognostic analysis, principal component analysis, and t-distributed stochastic neighbor embedding (t-SNE) analysis. Additionally, a nomogram model was devised, exhibiting promising potential in predicting OS patient prognosis. Further investigations incorporated gene set enrichment analysis to delineate active pathways in high- and low-risk groups. Furthermore, the impact of the risk prognostic model on the immune microenvironment of OS was evaluated through tumor microenvironment analysis, single-sample gene set enrichment analysis (ssGSEA), and immune infiltration cell correlation analysis. Drug sensitivity analysis was conducted to identify potentially effective drugs for OS treatment. Ultimately, the verification of the implicated ARGs in the model construction was conducted through the utilization of real-time quantitative polymerase chain reaction (RT-qPCR). Results: The ARGs risk prognostic model was developed, comprising seven high-risk ARGs (CBS, MYC, MMP3, CD36, SCD, COL13A1, and HSP90B1) and four low-risk ARGs (VASH1, TNFRSF1A, PIP5K1C, and CTNNBIP1). This prognostic model demonstrates a robust capability in predicting overall survival among patients. Analysis of immune correlations revealed that the high-risk group exhibited lower immune scores compared to the low-risk group within our prognostic model. Specifically, CD8+ T cells, neutrophils, and tumor-infiltrating lymphocytes were notably downregulated in the high-risk group, alongside significant downregulation of checkpoint and T cell coinhibition mechanisms. Additionally, three immune checkpoint-related genes (CD200R1, HAVCR2, and LAIR1) displayed significant differences between the high- and low-risk groups. The utilization of a nomogram model demonstrated significant efficacy in prognosticating the outcomes of OS patients. Furthermore, tumor metastasis emerged as an independent prognostic factor, suggesting a potential association between ARGs and OS metastasis. Notably, our study identified eight drugs-Bortezomib, Midostaurin, CHIR.99021, JNK.Inhibitor.VIII, Lenalidomide, Sunitinib, GDC0941, and GW.441756-as exhibiting sensitivity toward OS. The RT-qPCR findings indicate diminished expression levels of CBS, MYC, MMP3, and PIP5K1C within the context of OS. Conversely, elevated expression levels were observed for CD36, SCD, COL13A1, HSP90B1, VASH1, and CTNNBIP1 in OS. Conclusion: The outcomes of this investigation present an opportunity to predict the survival outcomes among individuals diagnosed with OS. Furthermore, these findings hold promise for progressing research endeavors focused on prognostic evaluation and therapeutic interventions pertaining to this particular ailment.

LAP2α orchestrates alternative lengthening of telomeres suppression through telomeric heterochromatin regulation with HDAC1: unveiling a potential therapeutic target.

In response to the challenge of telomere attrition during DNA replication, cancer cells predominantly employ telomerase or, in 10-15% of cases, the alternative lengthening of telomeres (ALT). The intricate details of ALT, however, remain elusive. In this study, we unveil that the knockdown of lamina-associated polypeptide 2 alpha (LAP2α) in ALT cells results in telomere dysfunction, triggering a notable increase in ALT-associated hallmarks, including high frequencies of PML bodies (APBs), C-rich extrachromosomal circles (C-circles), and telomere sister chromatid exchange (T-SCE). Furthermore, LAP2α emerges as a crucial player in break-induced telomere replication for telomerase-positive cells following telomeric double-strand breaks. Mechanistically, our investigation suggests that LAP2α may influence the regulation of the heterochromatic state of telomeres, thereby affecting telomeric accessibility. In line with our findings, LAP2α expression is markedly reduced in ALT-positive osteosarcoma. And the use of methotrexate (MTX) can restore the heterochromatin state altered by LAP2α depletion. This is evidenced by a significant inhibition of tumor proliferation in ALT-positive patient-derived xenograft (PDX) mouse models. These results indicate the important role of LAP2α in regulating ALT activity and offer insights into the interplay between lamina-associated proteins and telomeres in maintaining telomere length. Importantly, our findings may help identify a more appropriate target population for the osteosarcoma therapeutic drug, MTX.

HSPD1 Supports Osteosarcoma Progression through Stabilizing ATP5A1 and thus Activation of AKT/mTOR Signaling.

Malignant transformation is concomitant with excessive activation of stress response pathways. Heat shock proteins (HSPs) are stress-inducible proteins that play a role in folding and processing proteins, contributing to the non-oncogene addiction of stressed tumor cells. However, the detailed role of the HSP family in osteosarcoma has not been investigated. Bulk and single-cell transcriptomic data from the GEO and TARGET databases were used to identify HSPs associated with prognosis in osteosarcoma patients. The expression level of HSPD1 was markedly increased in osteosarcoma, correlating with a negative prognosis. Through in vitro and in vivo experiments, we systematically identified HSPD1 as an important contributor to the regulation of proliferation, metastasis, and apoptosis in osteosarcoma by promoting the epithelial-mesenchymal transition (EMT) and activating AKT/mTOR signaling. Subsequently, ATP5A1 was determined as a potential target of HSPD1 using immunoprecipitation followed by mass spectrometry. Mechanistically, HSPD1 may interact with ATP5A1 to reduce the K48-linked ubiquitination and degradation of ATP5A1, which ultimately activates the AKT/mTOR pathway to ensure osteosarcoma progression and EMT process. These findings expand the potential mechanisms by which HSPD1 exerts biological effects and provide strong evidence for its inclusion as a potential therapeutic target in osteosarcoma.

Unlocking the tumor-immune microenvironment in osteosarcoma: insights into the immune landscape and mechanisms.

Osteosarcoma has a unique tumor microenvironment (TME), which is characterized as a complex microenvironment comprising of bone cells, immune cells, stromal cells, and heterogeneous vascular structures. These elements are intricately embedded in a mineralized extracellular matrix, setting it apart from other primary TMEs. In a state of normal physiological function, these cell types collaborate in a coordinated manner to maintain the homeostasis of the bone and hematopoietic systems. However, in the pathological condition, i.e., neoplastic malignancies, the tumor-immune microenvironment (TIME) has been shown to promote cancer cells proliferation, migration, apoptosis and drug resistance, as well as immune escape. The intricate and dynamic system of the TIME in osteosarcoma involves crucial roles played by various infiltrating cells, the complement system, and exosomes. This complexity is closely associated with tumor cells evading immune surveillance, experiencing uncontrolled proliferation, and facilitating metastasis. In this review, we elucidate the intricate interplay between diverse cell populations in the osteosarcoma TIME, each contributing uniquely to tumor progression. From chondroblastic and osteoblastic osteosarcoma cells to osteoclasts, stromal cells, and various myeloid and lymphoid cell subsets, the comprehensive single-cell analysis provides a detailed roadmap of the complex osteosarcoma ecosystem. Furthermore, we summarize the mutations, epigenetic mechanisms, and extracellular vesicles that dictate the immunologic landscape and modulate the TIME of osteosarcoma. The perspectives of the clinical implementation of immunotherapy and therapeutic approaches for targeting immune cells are also intensively discussed.

Osteosarcoma and Langerhans Cell Histiocytosis in a Pediatric Patient with Lynch Syndrome: A Case Report.

CASE: Lynch syndrome (hereditary nonpolyposis colorectal cancer) is associated with extracolonic manifestations, but skeletal tumors are rare. Our patient, a 12-year-old boy with Lynch syndrome, developed osteosarcoma of the left femur. Treatment included cytotoxic chemotherapy, wide resection, and pembrolizumab. Two years later, he developed an aggressive lesion in the contralateral femur that was thought to be metastatic osteosarcoma but which histology revealed to be Langerhans cell histiocytosis. CONCLUSION: This case underscores the importance of advanced testing in patients with osteosarcoma and poor response to chemotherapy, and of tissue sampling when patients with a primary malignancy develop new bone lesions. LEVEL OF EVIDENCE: IV.

Radiofrequency ablation of bilateral splanchnic nerves in a 15-year-old patient with visceral abdominal pain cancer.

Pain, a prevalent and debilitating symptom in cancer patients, significantly diminishes the quality of life for both individuals and their families. Addressing this critical issue, our study presents the case of a 15-year-old diagnosed with synchronous multifocal multicentric osteosarcoma. We utilized radiofrequency ablation of bilateral splanchnic nerves, a strategy of multimodal pain and palliative care. This approach not only proved to be safe and effective but also markedly improved the patient's quality of life. Our findings shine a light of hope, emphasizing the paramount importance of innovative pain management in pediatric oncology, especially in the final stages of life. This case report highlights the unwavering dedication to excellence in relieving suffering, offering hope for patients grappling with cancer.

Pain is a common and serious problem for cancer patients, osteosarcoma is a type of bone cancer that often affects children. making life hard for them and their families. We used a therapy called radiofrequency ablation on specific nerves to manage the pain. In the case of the patient's abdominal pain, this therapy was safe, worked well, and greatly improved the patient's quality of life. Our findings show the importance of new pain management methods in helping children with cancer, helping them reduce pain, using fewer strong pain medications and helping children in this case in the final stage of life.

Targeting Bone Tumours with 45S5 Bioactive Glass.

Despite advances in treatment modalities, bone tumour therapies still face significant challenges. Severe side effects of conventional approaches, such as chemo- and radiation therapy, result in poor survival rates and high tumour recurrence rates, which are the most common issues that need to be improved upon. The aim of this study was to evaluate the therapeutic properties of 45S5 bioactive glass (BG) for targeting bone tumours. The viability of the cells derived from osteosarcoma, chondrosarcoma, and giant cell tumours was significantly reduced in the presence of 45S5-BG. In contrast, the viability of non-malignant osteoblast-like cells, chondrocytes, and bone marrow-derived stromal cells was not or only slightly affected. While alterations to the particle surface induced by heat treatment, acid etching, or incubation in a simulated body fluid had only minor effects on cytotoxicity, reducing the particle size or sintering the material significantly improved the cytotoxic effect of 45S5-BG. Further, using a chicken chorioallantoic membrane assay, the co-transplantation of 45S5-BG resulted in a significant reduction in tumour formation in vivo. Given the known positive effects of BGs on bone regeneration, our findings suggest that 45S5-BG holds great potential for the development of new and effective bone tumour therapies, with minimal side effects on non-malignant cells and simultaneous contribution to bone healing.

Global research trends and hotspots in metabolomics of osteosarcoma: a decade-spanning bibliometric and visualized analysis.

Object: Osteosarcoma is a malignant tumor originating from the bones, commonly found in children and adolescents, especially in rapidly growing bone areas such as the knees and upper arms. In this study, we aim to delineate the evolution and convergence of research themes in osteosarcoma metabolomics over the past decade, identify major contributors, and forecast emerging trends that could direct future research efforts. Method: The bibliometric method has been applied to systematically analyze the literature in the field of osteosarcoma metabolomics. The relevant literatures were collected from the Web of Science Core Collection, spanning from January 1, 2014, to December 31, 2023. Tools such as CiteSpace, Bibliometrix, and VOSviewer were used for the visual analysis of the collected literatures. The focused information includes institutions, journals, countries, authors, keywords, and citations. Result: Various aspects in the field of osteosarcoma metabolism were analyzed. Shanghai Jiao Tong University has published the most papers in the past ten years, followed by Central South University and Zhejiang University. Among the sources, the international journal of molecular sciences publishes the most articles, and oncotarget is the journal with the highest H index. According to Bradford's law, there are 34 core journals identified. A total of 5501 authors participated in the creation of papers in this field. The distribution of authors follows Lotka`s Law, and 85.3% of authors have only one article. 46% of the corresponding authors are from China, but most of these corresponding authors are not good at international cooperation. China also has the largest number of publications, followed by the United States. It can be confirmed that China dominates this field. Among the keywords, "expression" is the keyword that has received the most attention in the past ten years. All keywords can be divided into 9 clusters. Based on the explosive words and hot topics each year, we speculate that future research will focus on the tumor microenvironment, molecular mechanisms and autophagy, targeted therapies and inhibitors. Conclusion: In summary, this study comprehensively analyzed the current state of research in the field of osteosarcoma metabolism through bibliometric methods. The findings revealed the development trends and research hotspots in this field, which may provide valuable references for future research directions.

Development of non-pulmonary soft-tissue metastasis is not a poor prognostic indicator in dogs with metastatic appendicular osteosarcoma.

Objectives: To evaluate whether patient factors affect development of non-pulmonary soft-tissue metastases following treatment of canine appendicular osteosarcoma and to report and compare outcomes to those in dogs with pulmonary or osseous metastases. Animals and procedure: The records of 3 veterinary teaching hospitals were reviewed to identify dogs that received definitive treatment for a primary appendicular osteosarcoma lesion and chemotherapy between January 2010 and June 2022. Dogs with non-pulmonary metastases following initial treatment were included. Descriptive statistics were calculated to summarize signalment information, and metastasis and survival times were compared between groups using Kaplan-Meier survival analysis and log-rank tests. Results: Thirty-six and 109 dogs developed non-pulmonary soft-tissue metastases and pulmonary or osseous metastases, respectively, following initial treatment. No patient factors were significantly associated with development of non-pulmonary soft-tissue metastases. The median times to non-pulmonary soft-tissue metastasis or initial pulmonary or osseous metastasis were 220 and 169 d, respectively (P = 0.18); whereas overall median survival times were 250 and 270 d, respectively (P = 0.36). Conclusion: Dogs with non-pulmonary soft-tissue metastases had similar disease-free intervals and survival rates to dogs with typical pulmonary or osseous metastases.

Le développement de métastases des tissus mous non pulmonaires n'est pas un indicateur de mauvais pronostic chez les chiens atteints d'ostéosarcome appendiculaire métastatique. Objectifs: Évaluer si les facteurs liés au patient affectent le développement de métastases des tissus mous non pulmonaires après le traitement de l'ostéosarcome appendiculaire canin et rapporter et comparer les résultats à ceux des chiens atteints de métastases pulmonaires ou osseuses. Animaux et procédure: Les dossiers de 3 hôpitaux universitaires vétérinaires ont été examinés pour identifier les chiens qui ont reçu un traitement définitif pour une lésion d'ostéosarcome appendiculaire primaire et une chimiothérapie entre janvier 2010 et juin 2022. Les chiens présentant des métastases non pulmonaires après le traitement initial ont été inclus. Des statistiques descriptives ont été calculées pour résumer les informations descriptives, et les métastases et les temps de survie ont été comparés entre les groupes à l'aide d'une analyse de survie de Kaplan-Meier et de tests du rang logarithmique. Résultats: Trente-six et 109 chiens ont développé des métastases des tissus mous non pulmonaires et des métastases pulmonaires ou osseuses, respectivement, après le traitement initial. Aucun facteur lié au patient n'a été significativement associé au développement de métastases des tissus mous non pulmonaires. Les délais médians avant métastases des tissus mous non pulmonaires ou métastases pulmonaires ou osseuses initiales étaient respectivement de 220 et 169 jours (P = 0,18); tandis que les durées médianes de survie globale étaient respectivement de 250 et 270 jours (P = 0,36). Conclusion: Les chiens présentant des métastases des tissus mous non pulmonaires présentaient des intervalles sans maladie et des taux de survie similaires à ceux des chiens présentant des métastases pulmonaires ou osseuses typiques.(Traduit par Dr Serge Messier).

Survival and functional outcomes after hemiarthroplasty in children with proximal tibial osteosarcoma.

BACKGROUND: Treatment options for correcting limb-length discrepancy after limb-salvage reconstruction for proximal tibial osteosarcoma in children have several limitations. Therefore, we aimed to evaluate the feasibility, complications, prognosis, and clinical outcomes of reconstruction using hemiarthroplasty after tumor resection in pediatric patients with proximal tibial osteosarcoma. METHODS: We conducted a comprehensive retrospective analysis of the data of pediatric patients with osteosarcoma of the proximal tibia who underwent surgery between December 2008 and November 2018 at our center. We enrolled 49 consecutive patients who underwent hemiarthroplasty. The cruciate ligaments of all patients were reconstructed using special spacers, and the medial and lateral collateral ligaments of the knee and joint capsule were reconstructed using a mesh. Postoperatively, if the unequal length of both lower limbs exceeded 4 cm or knee instability occurred, a second-stage surgery was performed for limb lengthening and replacing the distal femoral prosthesis. We analyzed the oncological prognosis, complications of hemiarthroplasty, postoperative stability, and postoperative function. RESULTS: The follow-up period ranged between 11 and 159 months, with a median of 84 (62, 129) months. The overall 5-year survival rate was 83.2%. Thirty-nine patients survived at the end of the follow-up period with 34 prostheses (87.2%). The overall prosthesis survival rate was 87.4% after 5 years, indicating the long-term benefits of the procedure. Limb length was measured in 28 adult patients. The average limb-length discrepancy was 33 ± 15 mm with a median of 33 mm (21, 47); the femur and tibia caused a discrepancy of 8.5 ± 9.9 mm and 24.8 ± 15.5 mm, respectively. The patients had 30-135° of knee motion, with a mean of 82 ± 24°. The femoral tibial angle was greater on the affected side than on the healthy side, with a mean difference of 4.5°±3.6°. The Musculoskeletal Tumor Society (MSTS) score was 25 ± 3. Five patients underwent second-stage distal femoral prosthesis replacement, with mean MSTS scores of 24 ± 2 and 28 ± 1 before and after second-stage surgery, respectively. CONCLUSIONS: Hemiarthroplasty in children reduces limb-length discrepancy in adulthood by rebuilding cruciate ligaments, lateral collateral ligaments, and the joint capsule, thereby improving knee stability.

Enzymatic TET-1 inhibition highlights different epigenetic behaviours of IL-1ß and TNFα in tumour progression of OS cell lines.

Osteosarcoma (OS) is the most frequent primary malignant bone tumour, whose heterogeneity represents a major challenge for common antitumour therapies. Inflammatory cytokines are known to be necessary for OS progression. Therefore, to optimise therapy, it is important to discover reliable biomarkers by identifying the mechanism generating OS and investigating the inflammatory pathways that support the undifferentiated state. In this work, we highlight the differences of epigenetic activities of IL-1ß and TNFα, and the susceptibility of TET-1 enzymatic inhibition, in tumour progression of three different OS cell lines. Investigating DNA methylation of IL-6 promoter and determining its expression, we found that TET enzymatic inhibition influences proliferation induced by inflammatory cytokines in OS cell lines. Moreover, Bobcat 339 treatment blocks IL-1ß epigenetic action on IL-6 promoter, while only partially those of TNFα as well as inhibits IL-1ß-dependent epithelial-mesenchymal transition (EMT) process, but only partially those of TNFα. In conclusion, this work highlights that IL-1ß and TNFα have different effects on DNA demethylation in OS cell lines, making DNA methylation a potential biomarker of disease. Specifically, in IL-1ß treatment, TET-1 inhibition completely blocks tumour progression, while in TNFα actions, it is only partially effective. Given that these two inflammatory pathways can be therapeutic targets for treating these tumours, knowledge of their distinct epigenetic behaviours can be useful for developing precise and specific therapeutic strategies for this disease.

Reproducibility of spatial penalty-based methodologies for intravoxel incoherent motion analysis with diffusion MRI.

Objective was to assess the precision and reproducibility of spatial penalty-based intravoxel incoherent motion (IVIM) methods in comparison to the conventional bi-exponential (BE) model-based IVIM methods. IVIM-MRI (11 b-values; 0-800 s/mm2) of forty patients (N = 40; Age = 17.7 ± 5.9 years; Male:Female = 30:10) with biopsy-proven osteosarcoma were acquired on a 1.5 Tesla scanner at 3 time-points: (i) baseline, (ii) after 1-cycle and (iii) after 3-cycles of neoadjuvant chemotherapy. Diffusion coefficient (D), Perfusion coefficient (D*) and Perfusion fraction (f) were estimated at three time-points in whole tumor and healthy muscle tissue using five methodologies (1) BE with three-parameter-fitting (BE), (2) Segmented-BE with two-parameter-fitting (BESeg-2), (3) Segmented-BE with one-parameter-fitting (BESeg-1), (4) BE with adaptive Total-Variation-penalty (BE + TV) and (5) BE with adaptive Huber-penalty (BE + HPF). Within-subject coefficient-of-variation (wCV) and between-subject coefficient-of-variation (bCV) of IVIM parameters were measured in healthy and tumor tissue. For precision and reproducibility, intra-scan comparison of wCV and bCV among five IVIM methods were performed using Friedman test followed by Wilcoxon-signed-ranks (WSR) post-hoc test. Experimental results demonstrated that BE + TV and BE + HPF showed significantly (p < 10-3) lower wCV and bCV for D (wCV: 24-32%; bCV: 22-31%) than BE method (wCV: 38-49%; bCV: 36-46%) across three time-points in healthy muscle and tumor. BE + TV and BE + HPF also demonstrated significantly (p < 10-3) lower wCV and bCV for estimating D* (wCV: 89-108%; bCV: 83-102%) and f (wCV: 55-60%; bCV: 56-60%) than BE, BESeg-2 and BESeg-1 methods (D*-wCV: 102-122%; D*-bCV: 98-114% and f-wCV: 96-130%; f-bCV: 94-125%) in both tumor and healthy tissue across three time-points. Spatial penalty based IVIM analysis methods BE + TV and BE + HPF demonstrated lower variability and improved precision and reproducibility in the current clinical settings.

Make it STING: nanotechnological approaches for activating cGAS/STING as an immunomodulatory node in osteosarcoma.

Osteosarcoma is a highly aggressive bone cancer primarily affecting children, adolescents, and young adults. The current gold standard for treatment of osteosarcoma patients consists of two to three rounds of chemotherapy, followed by extensive surgical intervention from total limb reconstruction to amputation, followed by additional rounds of chemotherapy. Although chemotherapy has advanced the treatment of osteosarcoma significantly, the overall 5-year survival rate in resistant forms of osteosarcoma is still below 20%. The interaction between cancer and the immune system has long been recognized as a critical aspect of tumour growth. Tumour cells within the tumour microenvironment (TME) suppress antitumour immunity, and immunosuppressive cells and cytokines provide the extrinsic factors of tumour drug resistance. Emerging research demonstrates an immunostimulatory role for the cGAS/STING pathway in osteosarcoma, typically considered an immune-cold or immunosuppressed cancer type. cGAS/STING signalling appears to drive an innate immune response against tumours and potentiates the efficacy of other common therapies including chemo and radiotherapy. Nanotechnological delivery systems for improved therapy delivery for osteosarcoma have also been under investigation in recent years. This review provides an overview of cGAS/STING signalling, its divergent roles in the context of cancer, and collates current research which activates cGAS/STING as an adjuvant immunomodulatory target for the treatment of osteosarcoma. It will also discuss current nanotechnological delivery approaches that have been developed to stimulate cGAS/STING. Finally, it will highlight the future directions that we believe will be central to the development of this transformative field.

CircRNA TUBA1C promotes proliferation and glucose metabolism, and blocks apoptosis of osteosarcoma cells through sponging miR-143-3p.

Osteosarcoma (OS) is a malignant bone tumour that commonly occurs in paediatric and adolescent patients. Currently, effective therapy for OS remains elusive due to poor patient survival rates. In this study, we observed significantly elevated expressions of circTUBA1C in OS tumours and cells. Silencing circTUBA1C effectively suppressed proliferation and glucose metabolism, and promoted apoptosis of OS cells. Furthermore, we discovered that miR-143-3p played a reverse role to circTUBA1C in OS cells. Bioinformatics analysis, RNA pull-down assay, and luciferase assay demonstrated that circTUBA1C acted as a sponge for miR-143-3p, blocking its expression in OS cells. Finally, rescue experiments showed that inhibition of miR-143-3p in circTUBA1C-silenced OS cells significantly overrode the low-circTUBA1C-mediated miR-143-3p upregulation and OS cell progression in vitro and in vivo . Our results demonstrate the critical roles and molecular targets of circTUBA1C in modulating OS progression, suggesting that circTUBA1C inhibition could serve as a new therapeutic strategy for treating OS.

Metronomic chemotherapy for paediatric extracranial solid tumours: a systematic review and meta-analysis of randomised clinical trials.

BACKGROUND: Metronomic chemotherapy ('less is more, regularly') could be an alternative to the maximum tolerated dose ('the more, the better') in the chemotherapeutic cancer treatment of high-risk malignant solid extracranial tumours in children or young adults. OBJECTIVE: To evaluate the efficacy of metronomic chemotherapy compared with placebo or stop treatment in paediatric patients with extracranial malignant solid tumours. METHODS: We searched the databases MEDLINE and CENTRAL on 8 September 2023 and included randomised clinical trials (RCTs). Primary outcome was overall survival, and the main outcome measure was the HR. RESULTS: We identified three RCTs with parallel assignment and intention-to-treat analyses of data from 775 people. The studies primarily reported on participants with rhabdomyosarcoma, neuroblastoma and osteosarcoma. The HR favoured the metronomic chemotherapy group (0.75 (95% CI 0.56 to 0.98)). CONCLUSIONS: The evidence base is compatible with a favourable effect of metronomic chemotherapy on children and young adults with high-risk extracranial malignant solid tumours, especially other than bone tumours, when compared with placebo or stop treatment. Statistical heterogeneity is low while clinical heterogeneity is substantial. Thus, the results must be interpreted with caution and applicability of the results is limited. Future RCTs could provide more data on individual tumour entities and subsequently add information on tumour-specific responses. PROSPERO REGISTRATION NUMBER: CRD42023457195.

Epidemiology of bone tumors in children and adolescents: a retrospective study of 266 patients in the south of Tunisia.

Although bone tumors (BT) are relatively uncommon among the human neoplasm, they constitute the most frequent tumors in children and adolescents (CAA). Little information is available about the epidemiologic features of BT in CAA. We aimed to present and discuss epidemiological characteristics of BT in CAA in southern Tunisia, regarding the different histological types. This is a retrospective study including cases of BT in CAA collected in the pathology department at the Habib Bourguiba university hospital over a period of 15 years (2006- 2020). A total of 266 BT was diagnosed in our institution (42,7% among all BT in Southern Tunisia) divided into 200 benign bone tumors (BBT) (75,2%) and 66 malignant bone tumors (MBT) (24,8%). The mean age for all BT was 14,2 years (3-20 years) with male predominance (sex ratio: 1,48). The most common tumor was osteochondroma (42.2%) followed by osteosarcoma (14.6%) and Ewing sarcoma (6.4%). For BBT, the most affected age group was the 16 to 20 year - old - group (50,7%) with a male predominance (59.8%) and a predilection for lower limb (66.8%) then the upper limb (16,8%). Osteochondroma was the most common histological type (56.5%) followed by aneuvrysmal cyst (8,5%) and osteoid osteoma (6,5%). For MBT, the mean age was 12,5 years (5-20 years) and the most affected age group was the 11 to 15 year -old -group (59%). Boys were more affected (60.6%), with a preference for the lower limb (57%) followed by the pelvis (15,6%). Osteosarcoma was the most common MBT (60%) followed by Ewing sarcoma (24%). Given their rarity and heterogeneity, the diagnosis of BT is particular in CAA and requires a multidisciplinary approach. The reporting of epidemiological studies remains essential in order to expand our knowledge regarding these uncommon tumors.

Li-Fraumeni-associated osteosarcomas: The French experience.

PURPOSE: Describe clinical characteristics and outcome of Li-Fraumeni syndrome (LFS)-associated osteosarcomas. METHODS: TP53 germline pathogenic/likely pathogenic variant carriers diagnosed with osteosarcoma in France between 1980 and 2019 were identified via the French Li-Fraumeni database at Rouen University Hospital. Sixty-five osteosarcomas in 52 patients with available clinical and histological data were included. The main clinical characteristics were compared with data from National Cancer Institute's SEER (Surveillance, Epidemiology, and End Results) for patients of the same age group. RESULTS: Median age at first osteosarcoma diagnosis was 13.7 years (range: 5.9-36.7). Compared to unselected osteosarcomas, LFS-associated osteosarcomas occurred more frequently in patients less than 10 years of age (23% vs. 9%), and when compared with osteosarcomas in patients less than 25 years were characterized by an excess of axial (16% vs. 10%) and jaw sites (15% vs. 3%) and histology with predominant chondroblastic component and periosteal subtypes (17% vs. 1%). Metastases incidence (25%) was as expected in osteosarcomas. After the first osteosarcoma treatment, the rate of good histologic response (62%) and the 5-year progression-free survival (55%, 95% confidence interval [CI]: 42.6-71.1) were as expected in unselected series of osteosarcomas, whereas the 5-year event-free survival was 36.5% [95% CI: 25.3-52.7] due to the high incidence of second malignancies reaching a 10-year cumulative risk of 43.4% [95% CI: 28.5-57.5]. CONCLUSION: In osteosarcoma, young age at diagnosis, axial and jaw sites, histology with periosteal or chondroblastic subtype, and synchronous multifocal tumors should prompt suspicion of a germline TP53 mutation. Standard treatments are effective, but multiple malignancies impair prognosis. Early recognition of these patients is crucial for tailored therapy and follow-up.

Tetrahedral Framework Nucleic Acid-Loaded Retinoic Acid Promotes Osteosarcoma Stem Cell Clearance.

Metastatic osteosarcoma is a commonly seen malignant tumor in adolescents, with a five year survival rate of approximately 20% and a lack of treatment options. Osteosarcoma cancer stem cells are considered to be important drivers of the metastasis of osteosarcoma, and therefore their clearance is considered a promising strategy for treating metastatic osteosarcoma. In the relevant literature, retinoic acid (ATRA) is considered effective for eliminating osteosarcoma stem cells, but it has some inherent disadvantages, including poor solubility, difficulty in entering cells, and structural instability. Tetrahedral framework nucleic acids (tFNAs) are a type of nanoparticles that can carry small-molecule drugs into cells to exert therapeutic effects. Therefore, we designed and synthesized a nanoparticle named T-ATRA by using tFNAs to load ATRA and studied its effect in a nude mouse model. T-ATRA is more effective than ATRA in the clearance of osteosarcoma stem cells and in inhibiting osteosarcoma cell metastasis via the Wnt signaling pathway, thus prolonging the survival time of nude mice with osteosarcoma.