Adamantinoma-like Ewing sarcoma (ALES) is an exceedingly rare neoplasm, typically arising in the head and neck. We present a case of bladder tumour initially diagnosed as urothelial carcinoma on transurethral resection, which after neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin and cisplatin and subsequent radical cystoprostatectomy was reclassified as ALES with no residual urothelial carcinoma.

Osteosarcoma remains a major therapeutic challenge because of metastatic progression, recurrence and intrinsic or acquired resistance to conventional chemotherapy. Phytochemicals have emerged as potential complementary agents because of their ability to modulate multiple biological processes associated with osteosarcoma progression and treatment resistance. This review evaluates the mechanistic basis, pharmacological evidence and translational potential of phytochemical-drug combinations in osteosarcoma, with particular emphasis on redox regulation, DNA damage and repair, survival signalling, regulated cell death and metastatic progression. The available evidence indicates that phytochemicals can suppress osteosarcoma growth through apoptosis and cell-cycle arrest, while also modulating oxidative stress, ferroptosis, autophagy, epithelial-mesenchymal transition and oncogenic signalling pathways. Selected combinations with cisplatin or doxorubicin demonstrate enhanced chemosensitivity through modulation of pathways including PI3K/Akt, Wnt/β-catenin, STAT3, NF-κB and Nrf2/SLC7A11/GPX4, with ferroptosis emerging as a potential strategy for exploiting redox vulnerabilities in resistant disease. However, increased cytotoxicity or reduced chemotherapy IC50 values should not be interpreted as pharmacological synergy without quantitative combination analysis. Most evidence remains derived from conventional two-dimensional cell models, while poor bioavailability, uncertain tumour exposure, pharmacokinetic interactions and limited toxicity data remain important translational barriers. A Mechanism-Interaction-Translation framework is proposed to prioritize promising combinations based on biological vulnerability, quantitatively validated drug interaction and confirmation of efficacy and tolerability in increasingly relevant models. Overall, phytochemical-drug combinations represent a promising preclinical strategy for improving therapeutic responses in osteosarcoma, but further mechanistically validated, pharmacokinetically feasible and clinically relevant studies are required before their therapeutic efficacy can be established.

As a biodegradable material, magnesium‑gallium (Mg-xGa) alloy has exhibited outstanding antibacterial properties, however, its potential application in postoperative bone tumor repair still necessitates the validation of its antitumor function. In this study, Mg-xGa alloys (x = 0.5, 1.0, and 2.0 wt%) were successfully fabricated via conventional melting. The microstructure, biodegradation behavior, and tensile properties of the alloys were systematically characterized, followed by a comprehensive evaluation of their in vitro and in vivo biocompatibility and antitumor activity. Results demonstrated a uniform distribution of Ga as a solid solution in the Mg matrix, with no detectable second phases formed in the Mg-xGa alloys. Among the alloys, the Mg-2.0Ga alloy displayed optimal comprehensive tensile properties, coupled with a degradation rate of 0.134 mm/year. The Mg-xGa alloys effectively inhibited the proliferation and migration of U2OS and 143B bone tumor cells. This was associated with mitochondrial membrane potential depression, leading to the induction of apoptosis. In addition, the alloys exhibited favorable biocompatibility and osteogenic properties in vitro when co-cultured with MC3T3-E1 osteoblasts. Furthermore, in subcutaneous tumor models, they exhibited excellent antitumor activity and biocompatibility without significant systemic toxicity observed. In summary, the incorporation of an appropriate amount of Ga into Mg effectively inhibits tumorigenic activity in bone tumor cells while maintaining normal cellular functions in healthy cells. This Mg-xGa alloy exhibits broad application prospects in both bone tissue engineering and bone tumor therapy, warranting further exploration of their clinical value.

Triptolide, a bioactive diterpenoid epoxide isolated from Tripterygium wilfordii Hook. F. (Thunder God Vine), is a potent multi-target natural compound with significant anticancer potential. This systematic review with narrative synthesis evaluates preclinical evidence published between 2015 and 2026 on its molecular mechanisms, cancer-specific responses, and translational prospects, introducing a confidence-based framework to grade the strength of reported mechanisms. Across 51 studies, triptolide showed broad-spectrum anticancer activity in breast, lung, colorectal, pancreatic, hepatocellular, ovarian, prostate, glioma, and osteosarcoma models, acting mainly through mitochondrial apoptosis (92% of studies), reactive oxygen species generation, cell-cycle arrest, and modulation of NF-κB, PI3K/Akt/mTOR, STAT3, and Wnt/β-catenin signaling, with chemosensitization to cisplatin, gemcitabine, pemetrexed, and gefitinib reported in 31% of studies. Clinical translation, however, remains constrained by a therapeutic-index paradox: the same multi-target actions driving efficacy also underlie systemic toxicity, compounded by poor aqueous solubility, low bioavailability, and a narrow therapeutic window. The prodrug Minnelide has reached phase I/II trials, but substantial toxicity persists and no phase III data yet exist. Future progress will likely depend on improved delivery and toxicity-mitigation strategies rather than the discovery of additional molecular targets.

A 15-year-old girl who had previously undergone surgery and chemotherapy for non-metastatic chondroblastic osteosarcoma of the left fibula was evaluated with [18]F-fluorodeoxyglucose positron emission tomography/computed tomography ([18]F-FDG PET/CT) during routine follow-up while in clinical remission. Imaging demonstrated a 36 × 17 mm hypermetabolic lesion in the right occipital condyle maximum standard uptake value [(SUVmax): 16.5], with adjacent bone and soft-tissue extension, together with a concurrent [18]F-FDG-avid pulmonary nodule (SUVmax: 3.4). Shortly after imaging, the patient developed mild neck discomfort and right-sided tongue deviation, suggesting hypoglossal nerve involvement. Biopsy of the skull base lesion and histopathological evaluation of the pulmonary nodule confirmed metastatic chondroblastic osteosarcoma with concordant morphology and immunophenotype. The patient underwent biopsy of the occipital lesion, surgical excision, radiotherapy, and wedge resection of the pulmonary metastasis. Skull base involvement from osteosarcoma arising in the extremities is exceptional and is particularly rare in pediatric patients. This case highlights the complementary role of whole-body [18]F-FDG PET/CT in detecting atypical metastatic sites that may not be routinely assessed by conventional surveillance strategies. In addition, the focused literature review underscores the exceptional rarity of skull base involvement in pediatric chondroblastic osteosarcoma and supports the need for heightened awareness of uncommon metastatic patterns.

Osteosarcoma is a highly aggressive malignancy in which pulmonary metastasis remains the leading cause of mortality. Tumor cell-derived secretome, comprising extracellular vesicles and soluble factors, has been implicated in cancer progression and metastatic dissemination; however, the mechanisms regulating its functional properties remain incompletely understood. CD81, a member of the tetraspanin family, is widely recognized as a marker of extracellular vesicles and has been associated with tumor progression and metastasis. In this study, we investigated the role of CD81 in regulating the metastasis-promoting function of the osteosarcoma-derived secretome. Secretome was collected from 143B wild-type osteosarcoma cells and 143B CD81-knockout cells and applied to in vitro and in vivo models. Secretome derived from wild-type cells significantly enhanced tumor cell proliferation, migration and invasion, whereas secretome derived from CD81-knockout cells showed markedly attenuated effects. In endothelial cells, secretome from wild-type cells promoted angiogenic activity, which was markedly attenuated in CD81-knockout cells, indicating a role in modulating tumor-endothelial interactions. In vivo, repeated administration of secretome from wild-type cells induced the accumulation of CD11b-positive and S100A8/A9-positive cells in the lung and significantly increased pulmonary metastasis following tumor cell injection. In contrast, these effects were substantially reduced in mice treated with secretome from CD81-knockout cells. These findings identify CD81 as a tumor-cell-intrinsic determinant of whether the osteosarcoma secretome itself acquires metastasis-promoting bioactivity, distinct from previously identified downstream secreted effectors, and suggest that CD81 may represent a therapeutic target acting across both tumor and microenvironmental compartments.

Osteosarcoma is a primary malignant bone tumor with a well-established tendency for pulmonary metastasis; however, gastrointestinal (GI) involvement is exceedingly rare. Intra-abdominal metastases may occur years to decades after the initial diagnosis. Hematogenous spread, following pulmonary metastasis, is the presumed mechanism. Due to delayed presentation and atypical manifestations, recognition of GI complications in patients with a remote history of osteosarcoma is essential. In this report, we present a case of an 80-year-old male with chronic GI complications decades after original metastatic osteosarcoma diagnosis involving the stomach and colon. He described recurrent, dull, constant left lower quadrant abdominal pain associated with poor oral intake and constipation. Physical examination demonstrated focal left lower quadrant tenderness. CT abdomen and pelvis revealed dilated small bowel loops concerning for partial small bowel obstruction, while esophagram demonstrated esophageal dysmotility with mild reflux. These findings are linked to the sequelae of complications following initial metastatic osteosarcoma. The patient had a history of numerous surgeries and required continuous opioid use for pain management. Conservative management consisted of bowel rest, laxatives, and supportive care resulting in transient symptom improvement; however, symptoms recurred frequently following discharge, leading to multiple readmissions for recurrent obstructive and dysmotility-related symptoms. This case highlights several gastroenterological considerations. Metastatic osteosarcoma and further GI sequelae should remain within the differential diagnoses of chronic abdominal pain or bowel obstruction in patients with a remote history of osteosarcoma, even decades after initial treatment. For gastroenterologists, recognition of both structural and functional GI sequelae of osteosarcoma is critical to guide symptom-directed, nonoperative management strategies and reduce recurrent hospitalizations.

Focal periphyseal edema (FOPE) is a magnetic resonance imaging (MRI) finding centered on the closing physis of the adolescent knee and generally regarded as a benign, self-limiting manifestation of physiologic physeal fusion. To date, no report has described biopsy findings in FOPE, as the diagnosis has relied exclusively on imaging characteristics and clinical follow-up. An 11-year-old male competitive swimmer presented with a 2-month history of atraumatic right anterior knee pain. Radiographs were unremarkable. Laboratory studies showed no evidence of inflammation. MRI demonstrated T2-hyperintense signal on both sides of the distal femoral epiphyseal plate, with extension to the adjacent medial metaphyseal cortex and gadolinium enhancement suggestive of physeal destruction. Given the imaging appearance and a differential diagnosis of osteosarcoma, chondroblastoma, giant cell tumor, and osteomyelitis, an image-guided core needle biopsy was performed to exclude aggressive pathology. Histopathology demonstrated normal tissue without inflammatory or neoplastic cells, and cultures were sterile. These findings excluded malignancy and infection in the sampled tissue, and a presumptive diagnosis of FOPE was made, and the patient was managed expectantly. At 3-month follow-up, the patient was asymptomatic, and repeat MRI showed marked interval improvement of the previously noted findings, although faint residual signal persisted. In this case, biopsy served to exclude aggressive disease rather than to confirm a specific histologic pattern of FOPE, and the diagnosis was ultimately supported by the subsequent clinical resolution and imaging improvement. These findings support a conservative, noninvasive diagnostic and management approach when imaging findings are otherwise typical of this entity.

Osteosarcoma is an aggressive bone malignancy with a propensity for pulmonary metastasis, yet the molecular mechanisms linking protein homeostasis to epitranscriptomic regulation remain incompletely understood. Here, integrated transcriptomic, survival, protein-interaction, and CRISPR dependency analyses identified the deubiquitinase USP36 as a driver of osteosarcoma progression. USP36 was elevated in osteosarcoma datasets, and higher expression was associated with poorer survival in univariable analysis. Functional studies showed that USP36 depletion suppressed osteosarcoma-cell proliferation and invasion, whereas USP36 overexpression enhanced these phenotypes. Re-expression of wild-type USP36, but not the catalytically inactive C131A mutant, restored clonogenic growth and invasive capacity in USP36-deficient cells, indicating that its tumor-promoting effects depend on catalytic activity. Mechanistically, USP36 interacted with NAT10, prolonged NAT10 protein stability, and reduced K48-linked NAT10 polyubiquitination in cells. USP36 depletion decreased ac4C enrichment on KIF23 mRNA, accelerated KIF23 transcript decay, reduced KIF23 and β-catenin abundance, and impaired Wnt/β-catenin transcriptional activity. Importantly, wild-type NAT10, but not the catalytically inactive NAT10-G641E mutant, restored KIF23 ac4C enrichment, KIF23 expression, Wnt reporter activity, and clonogenic growth after USP36 depletion. TCF3 bound the USP36 promoter and positively regulated endogenous USP36 expression, whereas Wnt inhibition reduced USP36 transcription, supporting a reinforcing TCF3-USP36-NAT10-KIF23-Wnt regulatory relationship. In vivo, USP36 depletion reduced orthotopic tumor burden and experimental pulmonary metastatic colonization. Collectively, these findings identify USP36 as an upstream regulator of NAT10 stability and establish a mechanistic link between ubiquitin-dependent protein turnover and ac4C-mediated KIF23 mRNA stabilization in osteosarcoma. The USP36-NAT10-KIF23 axis may therefore represent a molecular vulnerability warranting further biochemical and clinical investigation.

Osteosarcoma is a highly malignant bone tumor characterized by significant clinical heterogeneity and poor prognostic outcomes. In this study, we integrated single-cell RNA sequencing data to characterize the landscape of genes related to N[4]-acetylcytidine (ac4C) modification. We calculated an acRG activity score and found that activity was predominantly enriched in osteoblastic cells. Using a machine learning framework, we constructed a six-gene prognostic signature termed acRGBS. This signature served as a robust and independent predictor of overall survival across multiple independent cohorts. Further analysis revealed that high acRGBS scores were associated with an immunosuppressive tumor microenvironment and increased immune evasion potential. Among the hub genes identified, S100A13 was highlighted as a potential driver of tumor progression. Functional experiments demonstrated that S100A13 knockdown significantly inhibited cell proliferation and reduced xenograft tumor growth in vivo. Mechanistically, S100A13 physically interacts with the mitochondrial calcium uniporter (MCU) to maintain mitochondrial calcium homeostasis. Silencing S100A13 led to mitochondrial calcium overload, which exacerbated oxidative stress and induced cell apoptosis. Finally, we showed that S100A13 knockdown significantly enhanced the anti-tumor efficacy of cisplatin treatment. These findings suggest that S100A13 is a promising therapeutic target and a valuable biomarker for risk stratification in patients with osteosarcoma.

Despite substantial treatment improvements, the 5-year survival rate for metastatic osteosarcoma (OS) is still as low as 20%. Immunocompetent genetic mouse models of OS have been introduced, enabling in vivo OS studies. Here, we present the ROCCIA mouse, a quintuple-mutant extension of these models that develops multifluorescent OS tumors, allowing distinct fluorescently labeled OS cell populations to be identified and traced both within tumors and in the circulation. In addition, this model enables postnatal inactivation of the p53 and Rb1 genes, thus resembling development and progression of OS in humans. Using this model, we show that osterix (Osx)-expressing fluorescent tumor cells appear in circulation upon OS development and predominate in lung metastases, thus representing a potential target for future therapies. We also show that the immunological landscape of this model's tumor microenvironment mimics the previously described human OS microenvironment. Therefore, this immunocompetent, quintuple mutant, multifluorescent mouse model represents a powerful resource to analyze OS tumor development and metastasis in real time and to test translational therapies.