Search Results (1,241)

Osteosarcoma, the most prevalent primary malignant bone tumor in children and adolescents, is characterized by high rates of metastasis, recurrence, and chemotherapy resistance, leading to suboptimal patient survival. The MDM2-p53 pathway plays a pivotal role in its tumorigenesis and progression, where dysregulation leads to loss of p53 function. This review systematically elucidates the molecular mechanisms of this pathway and summarizes diverse targeted therapeutic strategies, including small-molecule MDM2 inhibitors, mutant p53 reactivators, and innovative modalities such as gene therapy and Proteolysis Targeting Chimeras (PROTACs). Despite demonstrating potent preclinical activity with low IC₅₀ values, the clinical translation of these agents has faced significant challenges. Early-generation MDM2 inhibitors (e.g., RG7112, Idasanutlin) showed limited monotherapy efficacy and dose-limiting toxicities like thrombocytopenia, halting their development at early-phase clinical trials. In contrast, novel MDM2 inhibitors like APG-115 have advanced to Phase II trials, marking a significant breakthrough. Although not yet tested in dedicated osteosarcoma cohorts, their safety and efficacy in MDM2-amplified solid tumors provide a critical foundation for the development of precision medicine and combination regimens for osteosarcoma. Future efforts to accelerate drug development may leverage single-cell sequencing and AI-aided drug design to decipher osteosarcoma heterogeneity and optimize drug profiles for reduced toxicity. Full article

Kaposi’s Sarcoma-associated herpesvirus (KSHV) has been etiologically linked to several human cancers, including Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD). However, recent studies suggest that KSHV infection may also be associated with the development of other diseases or increased risks, such as KSHV inflammatory cytokine syndrome (KICS), diabetes, malaria, heart disease, and other cancers. In this review, we summarize these findings from clinical observations, epidemiological studies or laboratory research, though more studies are needed in these emerging areas. We believe that this work will enhance our understanding of the molecular mechanisms underlying KSHV pathogenesis and contribute to improving treatments for related human diseases. Full article

Osteosarcoma, the most common malignant bone tumor in young individuals, often exhibits poor outcomes due to MDM2-mediated suppression of the p53 pathway. Whereas conventional MDM2 inhibitors block the p53–MDM2 interaction but frequently induce compensatory MDM2 upregulation, proteolysis-targeting chimeras (PROTACs) directly degrade MDM2 and bypass this limitation. Here, we investigated the anticancer efficacy of two MDM2-targeting PROTAC compounds, CL0144 and CL0174, in osteosarcoma models. In Saos-2 and U2OS cells, both PROTACs efficiently induced MDM2 degradation, leading to activation of p53 or p73 signaling, increased reactive oxygen species production, apoptotic cell death, and marked reductions in viability. PROTAC treatment also significantly suppressed proliferation, colony formation, sphere formation, migration, and invasion. In vivo, xenograft assays demonstrated robust tumor growth inhibition following PROTAC administration. Collectively, these findings demonstrate that MDM2-targeting PROTACs exert strong antitumor effects by degrading MDM2 and disrupting downstream oncogenic pathways, supporting their potential as a promising therapeutic strategy for osteosarcoma. Full article

Background/Objectives: Tumor thrombus is an uncommon but serious finding in sarcoma, with limited pediatric data. While adult cases indicate a median survival of ~14 months, outcomes in children remain poorly understood. Methods: A retrospective review (1990–2025) was conducted at a single pediatric tertiary center. Patients <18 years with pathologically confirmed bone or soft tissue sarcoma and radiographic or histologic evidence of tumor thrombus were included. Minimum follow-up was 3 years or until end of life. The primary outcome was survival after tumor thrombus diagnosis. Results: Thirteen patients (nine males, four females) met the inclusion criteria. The median age at sarcoma diagnosis was 10.5 years. Osteosarcoma was the most common subtype (69.2%), with 76.9% of tumors arising in bone. Disease was localized in 53.8% and metastatic in 46.2% at presentation. Tumor thrombus was contiguous in 61.5% and noncontiguous in 38.5%. The median time from sarcoma diagnosis to death was 44.2 months; from tumor thrombus diagnosis to death, this was 15.2 months. The overall survival after tumor thrombus diagnosis was 30.8%. Conclusions: Pediatric sarcoma with tumor thrombus is associated with poor prognosis, and surgical intervention did not appear to result in long-term survival in this small series. Tumor thrombus may be noncontiguous from the primary tumor, emphasizing the importance of advanced imaging and its implications for treatment planning and counseling. Full article

(1) Background: Pelvic osteosarcoma accounts for a small proportion of osteosarcoma cases but is associated with significantly poorer outcomes than extremity tumors. This study evaluates contemporary survival outcomes and prognostic factors in a single-center cohort. (2) Methods: We retrospectively analyzed 56 patients with primary pelvic osteosarcoma treated between 2006 and 2019. Demographic characteristics, surgical margins, adjuvant therapies, local recurrence, metastasis, survival outcomes and the Musculoskeletal Tumor Society (MSTS) Score were assessed. Kaplan–Meier analysis was performed for overall survival (OS), including subgroup analyses by age and Enneking classification. (3) Results: Median age at surgery was 24 years. R0 margins were achieved in 96.4% of cases. OS at 1, 3, and 5 years was 69%, 54%, and 48%, respectively. Younger patients (≤25 years) showed significantly improved 5-year OS (68%) compared with older groups. Enneking classification showed limited prognostic discrimination. Metastatic disease at any time strongly predicted inferior survival (5-year OS 30% vs. 66%). The mean MSTS score one year after operation was 14.1 points. Functional outcome showed marked variability and was strongly influenced by patient age, extent of resection, reconstruction strategy, and postoperative complications. Younger patients and those undergoing limited or non-acetabular reconstructions achieved superior functional results, whereas complex endoprosthetic reconstructions and revision-requiring complications were associated with reduced MSTS scores. (4) Conclusions: Pelvic osteosarcoma continues to be associated with substantial morbidity and mortality. Younger age and absence of metastatic disease are strong predictors of improved survival. Functional outcomes are typically moderate; further advances are needed to improve results. Full article

This retrospective study evaluated 92 feline oral neoplasms diagnosed in Thailand to characterize neoplasm types, anatomical distribution, and clinically relevant associations. Epithelial neoplasms accounted for 73% of all neoplasms, with squamous cell carcinoma being the most common (67%). Other epithelial neoplasms such as ameloblastoma, amelanotic melanoma, and adenocarcinoma were uncommon. Mesenchymal neoplasms (27%) were more heterogeneous, encompassing fibrosarcoma, osteosarcoma, lymphoma, plasma cell tumors, and several rare entities. Cats with epithelial neoplasms were significantly older than those with mesenchymal neoplasms (11.0 ± 3.8 vs. 6.8 ± 4.1 years old; p < 0.001), while body weight, sex, clinical stage, and perioperative mortality did not differ between neoplasm types. Breed distribution varied by neoplasm origin, with epithelial neoplasms more common in domestic shorthair cats, and the maxillary gingiva was the most frequently affected site. Neoplasm size strongly correlated with disease stage, as neoplasms > 2 cm were associated with advanced stages, while neoplasms ≤ 2 cm were typically stage I. Antibiotic use was significantly more frequent in senior cats compared to mature/adult cats (p = 0.014). In summary, SCC is the most common oral tumor in cats, indicating the importance of routine oral examinations, particularly in senior cats. Full article

Marrow-isolated adult multilineage inducible (MIAMI) cells are a subpopulation of mesenchymal stem/stromal cells (MSC) with enhanced self-renewal, multilineage plasticity, and anti-inflammatory properties, suggesting that their extracellular vesicles (MIA-EVs) may confer advantages over conventional MSC-EVs. MIAMI cells were transcriptionally profiled and expressed regenerative markers, including PDGFRB, CDX2, and TERT. We report the first successful isolation and characterization of MIA-EVs. EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis, transmission electron microscopy, flow cytometry, and surface markers. Cargo analysis identified growth factors (IGFBP-1, HGF, VEGF-D) and 19 highly expressed miRNA targeting survival, regenerative, and immune regulatory pathways. MIA-EVs were efficiently internalized, enhanced keratinocyte wound closure and suppressed osteosarcoma proliferation in vitro. Conditioned MIA-EVs reshaped pathway weighting without altering core regulatory identity, as a conserved 15-miRNA backbone persisted across naïve, irradiated, and cytokine-primed states. In contrast, a 9-miRNA core shared with MSC-EVs defined a basal mesenchymal framework, while MIA-EVs expanded regenerative, survival, and immune network connectivity. Similar to embryonic stem cell (ESC)-EVs, both MIA- and cytokine-primed EVs promoted M2 macrophage polarization, selectively upregulating IL1R2 and PPARG/STAT1, respectively. Meanwhile, MSC-EVs induced heterogeneous responses. These findings establish MIA-EVs as a conditioning-resistant, systems-regulated, cell-free platform with regenerative, immunomodulatory, and cytoprotective potential under hostile microenvironments. Full article

Chondrosarcomas (ChSs) are mesenchymal chemo- and radiation-resistant tumors, representing the second most frequently diagnosed bone sarcoma after osteosarcoma and 20% of all bone sarcomas. Most of ChS patients have a good prognosis after complete surgical resection. Conversely, patients with inoperable disease, due to the tumor location or metastatic dissemination, represent a great clinical challenge due to the lack of effective therapeutic options. In this study, to the best of our knowledge, we document, for the first time in human ChS tissues, the existence of CD-31- and Podoplanin-negative vascular-like channels containing red blood cells, allowing us to hypothesize the occurrence of vasculogenic mimicry (VM) in ChSs. By using patient-derived ChS cells and a stabilized ChS cell line, we demonstrate that ChS cells are able to form in vitro tubules apparently similar to those formed by endothelial cells. Further characterization of these vessels revealed the pivotal role of the Urokinase Plasminogen Activator Receptor (uPAR) in mediating the capability of ChS cells to form VM. Finally, we provide evidence that, unlike bevacizumab, which did not exert any effect, the uPAR-derived antiangiogenic peptide RI-3 behaves as a potent inhibitor of VM. Full article

Background: Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. At present, multi-agent chemotherapy and surgery provide only limited effects and the prognosis for patients with recurrent or metastatic disease remains poor, with 5-year survival rates below 30%. These challenges highlight the need for innovative therapeutic approaches targeting osteosarcoma more effectively. Fenretinide, a synthetic derivative of all-trans retinoic acid, has shown significant antitumor activity in various cancers. In a recent high-throughput drug screening study, fenretinide emerged as the most active molecule against diffuse midline glioma over more than 3500 compounds. Fenretinide also demonstrated cytotoxic activity against osteosarcoma cell lines in vitro and in preclinical models and is endowed with a favorable safety and toxicity profile. However, its poor water solubility and limited bioavailability have hindered its clinical translation. To improve fenretinide bioavailability and enhance tumor exposure, different nanotechnology-based drug delivery systems have been proposed. Here we propose a tertiary complex made of fenretinide, bovine serum albumin, and hydroxypropyl-betacyclodextrin, indicated as BSAF. Methods: BSAF was evaluated for the main physico-chemical parameters such as hydrodynamic size, zeta potential, stability to drug leakage, and the biological effect on the osteosarcoma cell line MG63. Results: BSAF showed hydrodynamic size at the nanoscale, enhanced drug solubilization, high drug loading and size stability to dilution, characteristics that make this complex useful for targeted therapy. When tested on the MG63 osteosarcoma cell line, BSAF demonstrated significantly enhanced cytotoxicity, with half-maximal inhibitory concentration (IC₅₀) values ~50% lower than free fenretinide. The complex was more efficient than free fenretinide in inhibiting cell migration as demonstrated by wound healing assay. Live-cell imaging analyses revealed a cytostatic effect at sub-cytotoxic concentrations. Specifically, treatment with concentrations below the IC₅₀ resulted in significantly prolonged cell doubling time, decreased cell divisions, increased cellular sphericity and thickness, and decreased cell area. These morphological changes are more consistent with cell cycle arrest rather than apoptosis. These findings were corroborated by stable dry mass measurements, an indication of a cytostatic state rather than progressive cell death. In addition, cell motility parameters (e.g., instantaneous velocity, track speed, and displacement) at the single-cell and population level were markedly reduced at sub-IC₅₀ concentrations, further supporting a cytostatic phenotype. Conclusions: Collectively, the new BSAF complex showed promise as a potential therapeutic agent for treating osteosarcoma cancer, due to the favorable physico-chemical characteristics and the cytotoxic/cytostatic effects on MG63 cells. BSAF effects may be therapeutically valuable, particularly in preventing tumor recurrence by suppressing the proliferative and migratory potential of residual drug-resistant clones. Unlike conventional anticancer agents that mainly rely on cell death, fenretinide, when complexed, demonstrates a dual capacity to induce both cytotoxic and cytostatic responses, depending on concentrations, potentially overcoming multiple resistance mechanisms that are generally associated with tumor exposure to drug sub-cytotoxic concentrations. Full article

During recent decades, bone cancer-related diseases have remained hard to treat because of poor diagnosis, systemic toxicity, and restricted conventional treatments. Hence, the fabrication of functionalised nanoparticles offers a promising alternative by limiting side effects and improving therapeutic outcomes. In this study, zinc-substituted hydroxyapatite (Zn-HA) nanoparticles were fabricated from biogenic tuna fish bone waste via a thermal decomposition method and subsequently functionalised with Catharanthus roseus (CR) flower extract to synthesise a Zn-HA/CR nanocomposite. Structural and compositional characterisations verified Zn ions incorporation into the HA lattice and efficient CR-derived phytochemical functionalisation without altering the hexagonal HA phase. Compared to pure hydroxyapatite, the Zn-HA/CR nanocomposite exhibited improved surface morphology, enhanced swelling behaviour and degradation, and increased microhardness. The nanocomposite demonstrated significantly enhanced antibacterial activity against Staphylococcus aureus and Escherichia coli. The Zn-HA/CR nanocomposite also showed strong, dose-dependent antioxidant activity in DPPH assays. Furthermore, in vitro cytotoxicity studies using MG-63 (HOS) osteosarcoma cancer cells revealed that the proposed nanocomposite leads to pronounced morphological alterations and reduced cell viability. The prepared Zn-HA/CR nanocomposite would be a potential nanocomposite for enhanced antioxidant and anticancer activity, which highlights this composite as a multifunctional biomaterial platform for therapeutic applications. Full article

Background: Reconstruction of the proximal humerus after wide tumor resection is technically demanding, and traditional methods such as allograft–prosthetic composites, reverse shoulder arthroplasty, and metal implants are limited by graft unavailability, pediatric size mismatch, their high cost, and metal-related stress shielding. Polyether ether ketone (PEEK), with its modulus closer to cortical bone and radiolucency, offers a promising alternative. Building upon the success in craniomaxillofacial surgery and its favorable physical characteristics, we applied personalized 3D-printed PEEK implants for proximal humerus reconstruction. This study reports the first evidence of applying patient-specific 3D-printed PEEK implants in the proximal humerus. Methods: A retrospective cohort study was conducted on seven patients who underwent wide resection of primary malignant bone tumors of the proximal humerus, followed by reconstruction using patient-specific 3D-printed PEEK implants. Implant design was based on preoperative computed tomography (CT) imaging, incorporating contralateral humeral mirroring and computer-aided design. The implants were fabricated using fused deposition modeling (FDM) with medical-grade PEEK under stringent thermal control (nozzle temperature > 400 °C and heated build chamber), followed by a controlled annealing process to minimize internal stress, optimize polymer crystallinity, and enhance mechanical durability. Outcomes assessed included implant survival, oncologic control, shoulder range of motion, and functional outcomes measured using the Musculoskeletal Tumor Society (MSTS) score. The mean follow-up duration was 56.3 months. Results: All patient-specific PEEK implants were successfully manufactured and implanted with satisfactory geometric accuracy. Mechanical implant survival was 85.7% at final follow-up, with one implant fracture occurring at 28 months. No cases of deep infection, dislocation, loosening, or permanent neurovascular injury were observed. Local soft-tissue recurrence occurred in two patients (28.6%), without distant metastasis or tumor-related mortality. The limb-salvage rate was 100%. At final follow-up, the mean MSTS score was 23.0 ± 1.6. Shoulder motion was limited but comparable to outcomes reported for conventional anatomic megaprosthetic reconstructions. Conclusions: Patient-specific 3D-printed PEEK implants provide a feasible and oncologically safe option for proximal humerus reconstruction after tumor resection, with acceptable midterm implant survival and functional outcomes. The favorable elastic modulus and radiolucency of PEEK offer distinct biomechanical and imaging advantages over metallic implants. Further design optimization and larger prospective studies are warranted to enhance mechanical durability and functional restoration. Full article

Osteosarcoma is one of the most common malignant tumors that develop in the bone. Currently, surgery is often the best and most used approach, often preceded and followed by chemotherapy, which, however, carries serious short- and long-term side effects. Recently, much attention has been paid to natural compounds capable of inducing tumor cell death, reducing tumor and metastatic activity, and interacting with selective chemotherapy targeting tumor cells. Griffonia simplicifolia, a tropical African plant, has attracted attention because its extracts with bioactive chemicals have demonstrated multiple therapeutic uses. We show the antitumor properties of a Griffonia seed extract, obtained by maceration in a hydroalcoholic mixture (ethanol/water, 70/30, v/v, Gri70), on osteosarcoma cell lines, evaluating cytotoxicity, interaction with a pro-inflammatory signal (interleukin-1β), epigenetic activity of this signal on interleukin-6 gene expression, and interactions with an elective chemotherapeutic agent, doxorubicin. Although the extract did not have strong antiproliferative activity in the cell lines analyzed, we nevertheless observed that it was able to block proliferative and migration signals induced by interleukin-1β, as well as acting epigenetically by blocking the de-methylation of the interleukin-6 promoter and its expression. Furthermore, the extract did not appear to interfere with the antitumor activity of doxorubicin, and the interaction potentiated antimetastatic effects. These results indicate that Gri-70 extract may be useful as adjuvants to enhance the effect of doxorubicin, reducing the adverse effects associated with the increased EMT process of osteosarcoma cells that manage to overcome cell death induction. Indeed, metastasis represents the main cause of poor prognosis. Full article

(1) Background: This study evaluates the anticancer potential of a newly synthesized azomethine-based compound, 6,6′,5,8-Dioxa-2,11-diazadodeca-1,11-diene-1,12-diyl)bis(4-bromo-2-methoxyphenol) (B-134-0), against osteosarcoma (SAOS-2) cells, focusing on its effects on apoptosis and DNA-damage-related gene expression. (2) Methods: B-134-0 was synthesized via condensation and tested at eight concentrations (0.5–100 μg/mL) for 24, 48, and 72 h. Cytotoxicity was assessed through MTT assay, and gene expression levels of TP53, RAD51, BRCA2, CASP2, MYC, MDM2, CDKN1A, ERCC1, ATR, and PRKDC were quantified through qPCR using the ΔΔ_Ct method. Molecular docking and DFT analyses were performed to explore structural stability and protein interactions. (3) Results: B-134-0 exhibited strong time-dependent cytotoxicity (IC₅₀: 71.58, 54.36, and 12.59 μg/mL at 24, 48, and 72 h, respectively) and significantly modulated the expression of cell cycle and DNA-repair-associated genes. The compound notably downregulated TP53, RAD51, CASP2, MYC, and MDM2, while CDKN1A and BRCA2 showed relative upregulation, indicating activation of the DNA damage response. Docking results revealed strong binding affinity with BRCA2 and CDKN1A, consistent with experimental findings. (4) Conclusions: These results indicate that B-134-0 exhibits potent anticancer activity by modulating DDR and apoptosis pathways, with strong molecular stability, suggesting its promise as a therapeutic candidate for osteosarcoma. Full article

Objective: To compare the clinical prognosis of metal endoprosthetic reconstruction versus biological reconstruction in the treatment of limb osteosarcoma and to analyze associated prognostic factors. Methods: From October 2014 to October 2021, a retrospective study was carried out of patients with high-grade extremity osteosarcoma. Patients were categorized into two groups based on the type of reconstruction: endoprosthetic reconstruction and biological reconstruction. Demographic data and prognosis were systematically compared between the two groups. Furthermore, a Cox proportional hazards model was employed to evaluate the risk factors associated with recurrence and survival outcomes. Results: A total of 133 patients were enrolled in the study, comprising 88 patients in the endoprosthetic reconstruction group and 45 patients in the biological reconstruction group. The 5-year overall survival (OS) and disease-free survival (DFS) rates for the endoprosthetic reconstruction group were 76.2% and 70.5%, respectively, which were higher than those observed in the biological reconstruction group (64.3% and 60%). Additionally, the local recurrence rate was significantly higher in the biological reconstruction group compared to the endoprosthetic reconstruction group (17.8% vs. 2.3%, p = 0.004). Cox regression analysis revealed that pathological fracture (p = 0.034) and the biological reconstruction (p = 0.007) were independent risk factors for local recurrence. Conclusions: Endoprosthetic reconstruction may be preferable for patients requiring early functional recovery or presenting with pathological fractures. Biological reconstruction may be considered for younger patients with diaphyseal defects and demanding long-term functional requirements, albeit with elevated local recurrence risk. Individualized decision-making incorporating tumor location, patient age, and functional goals is essential. Full article

Copper and zinc nanoparticles have been suggested as potent anticancer agents, particularly against osteosarcoma, a highly aggressive bone cancer with limited treatment options. In order to avoid systemic toxicity, biomolecular carriers able to chelate metal ions and deliver them in a targeted manner to the vicinity of cancer cells need to be developed. Herein, we have used a histidine-containing, cyclic dipeptide as a carrier able to chelate stabilized copper and zinc nanoparticles. The cyclic peptide cyclo-(histidine-phenylalanine) (cHF) self-assembled into amyloid-type fibrils; morphological and structural characterization following metal addition confirmed the formation of cHF−CuNPs and cHF–ZnNPs. These composite nanoparticles demonstrated bacteriostatic activity against Escherichia coli and Staphylococcus aureus at the in vitro level. We evaluated the optimal concentration of cHF–metalNP complexes with limited cytotoxicity to L929 fibroblasts and high cytotoxic effects against MG-63 osteosarcoma cells. Their cytotoxicity was particularly pronounced at pH 6.4, which emulates the tumor microenvironment. The cHF peptide alone did not demonstrate significant antimicrobial or cytotoxic effects to both cell types, suggesting that it can act as a cytocompatible, pH-responsive carrier of metal ions with targeted dual functionality against both microbial infections and osteosarcoma cancer cells. Full article