Search Results (326)

Skeletal muscle regeneration depends on coordinated transitions of muscle stem cells (MuSCs), also known as satellite cells, from quiescence through activation and proliferative expansion to differentiation and fusion, while self-renewal replenishes the quiescent MuSC pool within a dynamically remodeled niche. Fibroblast growth factor (FGF) signaling regulates these transitions, but its effects vary as MuSCs and their niche change across regenerative stages. FGF output is shaped by ligand availability and extracellular presentation, fibroblast growth factor receptor (FGFR) isoform expression and coreceptor availability, receptor trafficking, intracellular feedback, and the state of the responding cell. Following acute injury, FGF inputs can support MuSC activation and expansion; signaling is subsequently reconfigured during differentiation, fusion, self-renewal, and return to quiescence. Aging-associated regenerative decline, chronic injury and dystrophic remodeling, denervation, and metabolic dysfunction disrupt this coordination and can uncouple FGF activity from productive repair. Rhabdomyosarcoma provides a distinct malignant context in which the FGF network is rewired to sustain oncogenic myogenic cell states. Here, we integrate molecular, cellular, and niche-level evidence across these settings to explain why FGF signaling produces divergent outcomes and to clarify how cellular context and timing should inform therapeutic modulation. Full article

Background/Objectives: Pediatric solid tumors (PST) are a biologically distinct group of malignancies whose developmental origins and molecular drivers differ substantially from those of adult cancers, with direct implications for therapeutic strategy and clinical outcome. This review synthesizes current evidence on molecular pathogenesis, tumor microenvironment biology, and the structural conditions that shape access to care across select PST. Methods: A narrative review of peer-reviewed literature was conducted primarily using PubMed, supplemented by Google Scholar, covering publications from 2000 to 2025. Tumor types were selected based on their prevalence in the pediatric population and the availability of evidence addressing both molecular features and health disparities. Body: Across eight tumor types (neuroblastoma, Ewing sarcoma, pediatric brain tumors, rhabdomyosarcoma, Wilms tumor, retinoblastoma, osteosarcoma, and chondrosarcoma), recurrent molecular alterations including MYCN amplification, EWS-FLI1 fusions, PAX-FOXO1 rearrangements and IDH 1/2 mutations emerge as central determinants of disease behavior and eligibility for treatment. The tumor microenvironment manifests as a shared mediator of immune exclusion and therapeutic resistance across tumor types, with, but not limited to, tumor-associated macrophages, myeloid-derived suppressor cells, and checkpoint molecule expression, identified as recurrent features influencing treatment response. Immunotherapeutic strategies have shown variable efficacy across PST, with the most consistent clinical benefit established in neuroblastoma. A critical and underappreciated pattern stands out across tumor types: children carrying the most aggressive molecular subtypes are disproportionately those with the least access to therapies those subtypes demand, emphasizing an overlap of biological and structural disadvantage that is also amplified in low- and middle-income countries, where late-stage presentation, treatment abandonment and limited access to molecular diagnostics compound the biological disadvantage. Conclusions: Within the eight PST reviewed, the most aggressive molecular subtypes and the greatest structural disadvantages converge in the same children; those carrying MYCN amplification, PAX-FOXO1 fusions, or EWS-FLI1 fusions are disproportionately those with the least access to the therapies their biology demands. Genomic and immunologic advances will only reach their full clinical potential when paired with inclusive trial data, diversified genomic databases, and most importantly, equitable access to biomarker-specialized therapies across all populations. Full article

Background: Pleomorphic rhabdomyosarcoma (RMS) is a rare, adult-predominant high-grade sarcoma that usually arises in the deep soft tissues of the extremities. Primary oral pleomorphic RMS is exceptionally rare, and detailed CT and MRI characteristics of oral pleomorphic RMS remain sparsely documented. Case Presentation: A 66-year-old woman presented with a two-month history of lower anterior tooth pain and progressive mandibular swelling, initially misdiagnosed and treated as a dental infection. CT and MRI revealed a 3.8-cm heterogeneously enhancing mass centered in the mandibular gingiva, with aggressive cortical destruction, diffusion restriction, and anterior floor-of-mouth extension; oral cavity cancer (squamous cell carcinoma) was initially favored on imaging. The patient underwent wide excision with segmental mandibulectomy and fibular osteocutaneous free-flap reconstruction. Histopathologic examination confirmed a high-grade pleomorphic RMS with immunoreactivity for desmin and MyoD1. The patient received adjuvant chemotherapy and radiotherapy, with no recurrence at 8-month follow-up. Conclusions: Pleomorphic RMS of mandibular gingiva may be mistaken clinically for odontogenic infection and radiologically for squamous cell carcinoma. Although imaging findings are nonspecific, CT and MRI are essential for defining mandibular and floor-of-mouth involvement and planning resection; definitive diagnosis requires histopathologic and immunohistochemical confirmation. Full article

Therapeutic resistance remains a critical obstacle in rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma. Increasing evidence implicates redox adaptation in tumor survival and treatment failure. Here, we investigated the functional role and clinical relevance of catalase, a primary hydrogen peroxide-detoxifying enzyme, in modulating RMS therapeutic response. Integrated transcriptomic analyses revealed that while catalase is overall downregulated in RMS compared to healthy skeletal muscle, elevated expression strongly correlates with high-risk, metastatic disease and poor overall survival. In human RMS cell lines, catalase was detectable, and its pharmacological inhibition using 3-amino-1,2,4-triazole (3-ATA) promoted reactive oxygen species (ROS) accumulation, sensitizing cells to standard chemotherapeutics. Notably, robust catalase upregulation was observed in RMS cell models characterized by intrinsic and acquired radioresistance, with strong immunoreactivity validated on cell-block sections. Immunohistochemical validation across patient specimens revealed generally weak catalase expression in RMS tumors, whereas strong reactivity was observed in a secondary embryonal RMS (ERMS) arisen following chemoradiotherapy for nasopharyngeal carcinoma. Functionally, targeting catalase with 3-ATA restored both radio- and chemosensitivity in radioresistant RMS lines. Furthermore, co-targeting catalase and Akt using sub-toxic doses of 3-ATA and MK-2206 cooperatively enhanced oxidative stress-mediated cytotoxicity in resistant cells. Together, these findings identify catalase as a pivotal driver of adaptive radioresistance and establish dual catalase/Akt targeting as a promising pro-oxidant strategy to overcome radiotherapy resistance in RMS. Full article

Ewing sarcoma is a highly malignant tumor whose histological appearance often overlaps with that of other undifferentiated round-cell and ovoid-cell tumors, making accurate diagnosis challenging. Selecting the most appropriate immunohistochemical and molecular tests is critical, particularly when only limited core biopsy material is available and tissue preservation for additional molecular or biomarker testing is required. Artificial intelligence (AI)-based histopathological image analysis is emerging as a promising diagnostic tool in oncology. This study evaluated the potential of AI-based histopathological analysis to assist pathologists in the morphologic classification of Ewing sarcoma and selected histological mimics using tissue microarrays (TMAs), rather than to identify or predict molecular alterations. We analyzed 1926 digitized histological cores, from 729 patients, assembled into 45 tissue microarrays. The dataset comprised 517 Ewing sarcomas (ESs), 367 rhabdomyosarcomas (RMSs), 187 chondrosarcomas (CHSs), 138 gastrointestinal stromal tumors (GISTs), and 124 synovial sarcomas (SSs). A weakly supervised multiple-instance learning (MIL) framework with transformer-based aggregation was developed using only core-level diagnostic labels. The model achieved classification accuracies of 97.1% for Ewing sarcoma, 80.0% for rhabdomyosarcoma, 85.7% for gastrointestinal stromal tumors, 80.0% for chondrosarcoma, and 76.0% for synovial sarcoma. The overall classification accuracy was 91.6%, with no misclassifications between Ewing sarcoma and rhabdomyosarcoma. These findings highlight the model’s robustness in distinguishing tumor entities that present a well-recognized diagnostic challenge in routine pathology. The AI algorithm demonstrated strong potential as a diagnostic adjunct for assisting pathologists in the morphologic classification of Ewing sarcoma and selected tumor entities based on histopathological features. Although these tumor entities are characterized by specific molecular alterations, the model was not designed to identify or predict molecular alterations directly. Instead, it supports clinical decision-making by recognizing morphologic patterns associated with diagnostically defined tumor entities. The integration of AI-based histopathological analysis with immunohistochemistry and contemporary molecular diagnostic techniques has the potential to improve diagnostic accuracy, optimize the use of ancillary testing, enhance our understanding of genotype–phenotype relationships, and ultimately support more effective patient management. Full article

Background/Objectives: Fusion-positive rhabdomyosarcoma (FP-RMS) is characterized by the presence of tumor-specific chromosomal translocation products, most commonly PAX3::FOXO1, and typically results in lower survival rates compared to fusion-negative RMS cases. PAX3::FOXO1 plays a critical role in FP-RMS oncogenesis in both tumor initiation and maintenance, making it an excellent target for therapeutic intervention in FP-RMS. Methods: We created Proteolysis Targeting Chimeras (PROTACs) by combining PAX3::FOXO1-binding small molecules with E3 ligase recruiters for cereblon (CRBN) or S-Phase Kinase Associated Protein 1 (SKP1). Results: The PROTACs achieved up to 70% degradation of the endogenous PAX3::FOXO1 protein in FP-RMS cell lines in a concentration-, time-, and proteasome-dependent manner. Moreover, the PROTAC-mediated targeted degradation of PAX3::FOXO1 in FP-RMS cells deregulated the endogenous PAX3::FOXO1 gene expression signature and induced myogenic differentiation. Importantly, treatment of FP-RMS cells with PAX3::FOXO1-PROTACs synergized with vincristine treatment and impaired >80% of anchorage-independent growth in soft agar. Conclusions: Taken together, we demonstrate the proof of principle of PROTACs targeting the oncogenic fusion protein PAX3::FOXO1 in FP-RMS cells. The PROTACs created in this study will not only be useful tools in studying PAX3::FOXO1 biology in laboratory models but could also serve as molecular scaffolds for designing clinical-grade molecules to assess the therapeutic potential of PAX3::FOXO1-targeting PROTACs in FP-RMS patients. Full article

Background/Objectives: Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, includes two main subtypes, embryonal (eRMS) and alveolar (aRMS), each with distinct molecular and clinical characteristics. Although cellular processes underlying RMS and differences between PAX3-FOXO1 fusion-positive and fusion-negative tumors are well known, the contribution of long noncoding RNAs (lncRNAs) remains poorly understood. Methods: Here, we reannotated publicly available microarray datasets to comprehensively profile lncRNA expression and reconstruct lncRNA–miRNA–mRNA regulatory networks in RMS. Results: We identified several lncRNAs with subtype-specific differential expression, including HOTAIR as a potential sponge for miR-206, DSCR8 for miR-885-5p, and PRKCQ-AS1 for miR-515-5p in eRMS. Database-supported interaction analyses identified putative regulatory relationships between these lncRNAs and cancer-related miRNAs and mRNAs. Validation using the St. Jude Cloud PeCan platform confirmed distinct lncRNA expression signatures across RMS subtypes and other pediatric solid tumors, supporting subtype-specific regulation. Conclusions: Our findings provide an updated characterization of the lncRNA landscape in RMS and identify candidate lncRNA–miRNA–mRNA regulatory networks that may contribute to disease biology. The proposed regulatory interactions are hypothesis-generating and require experimental validation. Overall, our findings provide a resource for future functional studies and support the investigation of lncRNAs as potential biomarkers and therapeutic targets in RMS. Full article

Background: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma, with survival dependent on risk stratification and multimodal therapy. This single-center study explored the clinical characteristics, treatment outcomes and prognostic factors of pediatric RMS to optimize local management. Methods: Data of RMS patients treated at Shanghai Children’s Hospital from 2011 to 2024 were analyzed to estimate event-free survival (EFS) and overall survival (OS), and factors associated with survival. Patients received the Rs-99 (pre-2019) regimen or a modified Rs-2018 (post-2019) regimen. Results: A total of 76 RMS patients were identified. The 5-year EFS and OS for the entire cohort were 71.1% (95% CI, 62.3% to 83.3%) and 72.4% (95% CI, 64.0% to 84.5%), respectively. No statistically significant differences were observed in EFS and OS between the Rs-2018 and Rs-99 regimens. Univariate survival analysis indicated that metastasis was associated with prognosis: the 5-year EFS and OS of patients with metastatic disease were 35.0% (95% CI, 18.3% to 57.6%) and 40.0% (95% CI, 27.3% to 75.3%), while both the 5-year EFS and OS of patients with localized disease reached 83.9% (95% CI, 69.3% to 93.6%). Primary tumor resection status was a key prognostic factor for patients with localized disease, with a 5-year EFS of 100% for R0 resection and 46.7% (95% CI, 25.2% to 74.0%) for R2 resection. For patients with localized disease, EFS was comparable between those who underwent delayed primary excision (DPE) and upfront resection. Conclusions: Outcomes for patients with metastatic RMS remain poor. For those with localized disease, primary tumor resection status correlates with improved EFS and OS; additionally, DPE represents a feasible therapeutic option for localized RMS involving complex anatomical sites. Full article

Rhabdomyosarcoma (RMS) confined to the bone marrow represents an exceptionally rare and aggressive presentation that can mimic primary hematological malignancies, often leading to diagnostic delays and therapeutic challenges. We report the case of a 34-year-old woman who presented with clinical and laboratory findings highly suggestive of a hematological disorder, including cytopenias and diffuse bone marrow involvement. Initial evaluation raised suspicion for leukemia; however, comprehensive diagnostic work-up, including immunohistochemistry and molecular studies, ultimately confirmed the diagnosis of PAX3/FOXO1 gene-rearranged alveolar RMS isolated in the bone marrow, with no identifiable primary soft tissue mass. The patient was treated with an intensive multi-agent chemotherapy regimen, resulting in a marked hematological recovery and a significant radiological improvement after a limited number of cycles. We further reviewed the limited literature on bone-marrow-confined RMS, highlighting the proposed pathophysiological mechanisms, diagnostic pitfalls, and reported treatment strategies. Given the absence of standardized management guidelines for this rare entity, therapeutic approaches are often extrapolated from conventional RMS protocols or regimens used for high-grade sarcomas. Our experience supports the potential efficacy of intensive chemotherapy in achieving meaningful clinical responses. This case report emphasizes the challenges in the diagnosis of RMS confined to the bone marrow due to its atypical presentation. It also highlights the poor prognosis and aggressiveness of this entity compared to conventional RMS. Full article

Background/Objectives: Transition metal complexes of imidazoles exhibit a variety of biological activities. This makes them promising metal-based drugs for use in medicine. The aim of this research is to investigate the complexes of zinc(II) with N-vinyl, N-allyl, and N-propargylimidazoles, represented by the formula [ZnL₂Cl₂], as potential drug candidates. Methods: Structural studies of the obtained complexes were performed using single-crystal X-ray diffraction analysis, IR and NMR spectroscopy. DFT calculations were used to determine structural, electronic and thermochemical parameters of the complexes. QSAR analysis was performed using PASS. The wound-healing and antihypoxic activities were studied in vivo using models of wounds and acute hypoxia of various origins. The antimicrobial activity of the complexes was evaluated against Staphylococcus aureus Wood 46, Escherichia coli M-17, and the yeast fungus Candida albicans 927. The cytotoxic activity was tested using several cell lines, including monkey kidney (Vero) cells, human cervical cancer cells (Hep2C and HeLa), human lung carcinoma (A549), and human embryonal rhabdomyosarcoma (RD). Results: New complexes of N-allylimidazole and N-allyl-2-methylimidazole with ZnCl₂ were synthesized and characterized. All the studied complexes possess diverse biological activities. While the antimicrobial activity was modest, a distinct antifungal activity was observed. The cytotoxicity of the complexes was found to be mainly in relation to Hep2c and RD cell lines. Conclusions: Based on the results of QSAR analysis and experimental findings, the diverse biological activities of the compounds indicate that they are promising lead structures for further optimization in drug development. Full article

Background: Orbital rhabdomyosarcoma (RMS) is the most common primary pediatric malignant orbital tumor, typically curable with chemotherapy and radiation. Data regarding MRI chemotherapy response and long-term ophthalmologic outcomes remain limited in non-cooperative-group settings. Methods: We retrospectively reviewed children with primary orbital RMS treated at King Hussein Cancer Center (2002–2025) with vincristine, actinomycin-D, and cyclophosphamide (VAC). Pre-local-control MRI responses were classified as complete (CR), partial (PR), stable/minor (SD/MR), or progressive disease (PD). Survival and ophthalmologic outcomes were analyzed. Results: Twenty-two patients (median age 5.6 years) were included. All had localized disease (77% low-risk). All received VAC; 20 (91%) received radiotherapy (median 45 Gy). Pre-radiotherapy MRI showed 8 (36%) CR and 11 (50%) PR. Four patients (18%) died. Five-year event-free survival (EFS) and overall survival (OS) were 73% and 84%, respectively. Cataracts developed in 45% of the cohort (50% of irradiated patients) at a median of 39.1 months (range 9.4–95.1). At last assessment, visual acuity was good in 60%, moderate in 25%, and severely impaired in 15%. Conclusions: Excellent survival in orbital RMS is achievable in resource-stratified settings. Induction MRI progressive disease (PD) was associated with poor outcomes in this cohort and may represent an early prognostic signal warranting further validation in larger studies. Furthermore, the documented maximum cataract latency of 95 months suggests that the standard 5-year surveillance window is insufficient. These findings support extending ophthalmologic surveillance beyond the standard 5-year window. We propose, based on our retrospective institutional data, a 10-year functional survivorship framework. Full article

Background: Accurate staging is vital for optimizing outcomes in pediatric rhabdomyosarcoma (RMS). While [¹⁸F]-FDG PET/CT is increasingly utilized, its specific impact on clinical management and its prognostic value compared to conventional imaging (CI) require further evaluation. Methods: In this retrospective single-center study, we reviewed 56 pediatric patients with RMS who underwent [¹⁸F]-FDG PET/CT at our center. Imaging findings were compared with CI (CT/MRI) and correlated with clinical management and survival outcomes. Results: In the total cohort (n = 56), PET/CT demonstrated high concordance with CI for nodal assessment, with an apparent sensitivity of 89.5% and specificity of 94.6%. PET/CT identified skeletal metastases in 5 patients (8.9%) and correctly characterized suspicious pulmonary nodules in one case, though it failed to detect a 0.6 cm lung nodule visualized on chest CT. Notably, PET/CT findings directly altered clinical management in 16.1% of patients (n = 9), primarily through radiotherapy adjustments, including field expansions (n = 4), field reductions (n = 3), and the initiation of previously unplanned radiotherapy (n = 2). At a median follow-up of 33.3 months, an exploratory analysis showed that patients with an SUVmax ≥3.6 had a lower 3-year EFS (57.6% vs. 71.6%; p = 0.51) and OS (60.4% vs. 71.6%; p = 0.63); neither comparison reached statistical significance. Conclusion: [¹⁸F]-FDG PET/CT is a powerful adjunct in pediatric RMS staging, particularly for nodal and skeletal evaluation. Its ability to refine radiotherapy planning in nearly one-sixth of cases underscores its clinical utility. SUVmax is not a validated prognostic or predictive biomarker in pediatric RMS; prospective, adequately powered multicenter studies, ideally incorporating volumetric PET parameters, are needed before any role in risk-stratified therapy can be defined. Full article

Objectives: This study evaluates the epidemiological characteristics and survival, functional, and esthetic outcomes of pediatric patients diagnosed with head and neck sarcoma (PHNS) who underwent individualized surgical treatment for local disease control and/or for defect reconstruction. Methods: A cohort of 45 patients aged 0–18 years with histologically confirmed PHNS who underwent surgical resection and/or reconstructive procedures was analyzed. Extracted variables included demographic data, tumor histology and stage, surgical margin status, and systemic therapy modalities. Reconstructive strategies were assessed, considering technique, sequencing, and total duration of treatment. Survival analysis was performed, focusing on both overall survival (OS) and event-free survival (EFS). Results: Rhabdomyosarcoma constituted the predominant diagnosis (19/45), followed by Ewing sarcoma (7/45) and chondrosarcoma (5/45). The maxilla represented the most common primary site (18/45), whereas orbital origin was the least frequent (3/45). Complete surgical excision (R0) was achieved in 80.5% of resected cases. Margin status showed no statistically significant association with final outcome (p = 0.7786). In contrast, nodal metastasis, local recurrence, and distant dissemination were independently and collectively correlated with mortality. Survival analysis demonstrated a 3-year OS of 100% and an EFS of 79.8%, and a 5-year OS of 94.7% with an EFS of 70.7%. Conclusions: Implementation of an individualized surgical and reconstructive protocol was associated with effective local tumor control and favourable reconstructive outcomes. Oncologic prognosis was driven primarily by nodal involvement and recurrent or metastatic disease rather than margin status alone. Full article

Background/Objectives: To study the hypothesis that cognitive functions and learning skills are impaired in child/adolescent childhood cancer survivors (CCS). Secondary outcomes included psychosocial parameters and quality of life. Methods: This case–control study was conducted over four years (2017–2021) at the largest pediatric Aghia Sophia Children’s Hospital, in Greece. Eligible participants were children and adolescents in Greece. For CCS, ≥1 year should have elapsed from completion of cancer treatment. Assessments of neurocognitive function, learning and psychosocial skills and health-related quality of life (HRQoL) were performed with validated instruments (WISC-III, LAMDA software, Achenbach CBCL/6-18 and YSR, KIDSCREEN-52, respectively). Results: In total, 219 participants (47.49% males, mean age ± SD 11.72 ± 2.32 years), 70 CCS and 149 controls (matched for age, sex, family income), were included. Cases were CCS of acute lymphoblastic leukemia (n = 25)/brain tumors (n = 19)/lymphoma (n = 17)/nephroblastoma (n = 5)/Ewing sarcoma (n = 3)/rhabdomyosarcoma (n = 1). CCS had worse scores in full-scale Intelligence Quotient (FSIQ) (p = 0.004), verbal IQ (VIQ) (p = 0.005) and all its subscales, performance IQ (PIQ) (p = 0.021), and almost all learning parameters than controls. Attention, working memory, writing/visual–motor coordination, processing accuracy/speed, language acquisition/expression, all psychosocial scales, and HRQoL domains of mood and emotions, were negatively affected in CCS. Female CCS demonstrated lower FSIQ (p = 0.019) and VIQ (p = 0.014) than control females, whereas male CCS retained their total IQ unaffected. Among CCS, those with non-central nervous system (CNS) tumors, higher parental educational level or higher family income had significantly higher IQ than those with CNS tumors, lower parental educational level or lower family income, respectively. Conclusions: CCS in Greece carry a significant burden of cognitive and psychological morbidity. Cognitive/educational and psychosocial support to CCS is imperative. Full article

PAX3 plays a vital role in regulating proper growth, migration, differentiation, and survival during development of normal tissues, including those derived from the embryonic neural crest. PAX3 is a transcription factor with two separate DNA-binding domains and can positively (and less frequently, negatively) regulate gene expression. The levels of PAX3 can be modified by upstream molecular pathways, and its subsequent downstream functions are regulated through a wide range of protein interactions and posttranscriptional modifications. PAX3 direct downstream target genes are other transcription regulators and factors that modulate cellular proliferation, lineage specificity, migration, and survival. The pathways that PAX3 regulates during development may be recycled and subverted during disease progression, for example, during cancer progression, growth, and metastasis. Indeed, PAX3 is overexpressed in several cancers, including melanoma, neuroblastoma, and rhabdomyosarcoma. While there is still much that is unknown about the mechanisms by which PAX3 controls such a wide array of key cellular functions, a great deal of progress has been made to advance our understanding of this critical and multi-faceted factor. Full article