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Radiologia 2016Rhabdomyosarcoma is the most common soft-tissue sarcoma in children; it can appear in any part of the body. Its biological behavior varies widely, and despite the... (Review)
Review
Rhabdomyosarcoma is the most common soft-tissue sarcoma in children; it can appear in any part of the body. Its biological behavior varies widely, and despite the absence of specific clinical or radiological characteristics, rhabdomyosarcoma should be taken into account in the differential diagnosis of solid tumors in children. This review focuses primarily on the imaging findings and anatomical distribution of the histological subtypes of childhood rhabdomyosarcoma and secondarily on the differential findings in histological studies.
Topics: Child; Humans; Rhabdomyosarcoma, Embryonal
PubMed: 27810092
DOI: 10.1016/j.rx.2016.09.003 -
Journal of Clinical Oncology : Official... Sep 2021Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite aggressive therapy, the 5-year survival rate for patients with metastatic or recurrent...
PURPOSE
Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite aggressive therapy, the 5-year survival rate for patients with metastatic or recurrent disease remains poor, and beyond fusion status, no genomic markers are available for risk stratification. We present an international consortium study designed to determine the incidence of driver mutations and their association with clinical outcome.
PATIENTS AND METHODS
Tumor samples collected from patients enrolled on Children's Oncology Group trials (1998-2017) and UK patients enrolled on malignant mesenchymal tumor and RMS2005 (1995-2016) trials were subjected to custom-capture sequencing. Mutations, indels, gene deletions, and amplifications were identified, and survival analysis was performed.
RESULTS
DNA from 641 patients was suitable for analyses. A median of one mutation was found per tumor. In fusion-negative cases, mutation of any RAS pathway member was found in > 50% of cases, and 21% had no putative driver mutation identified. (15%), (15%), and (13%) mutations were found at a higher incidence than previously reported and mutations were associated with worse outcomes in both fusion-negative and fusion-positive cases. Interestingly, mutations in isoforms predominated in infants < 1 year (64% of cases). Mutation of was associated with histologic patterns beyond those previously described, older age, head and neck primary site, and a dismal survival. Finally, we provide a searchable companion database (ClinOmics), containing all genomic variants, and clinical annotation including survival data.
CONCLUSION
This is the largest genomic characterization of clinically annotated rhabdomyosarcoma tumors to date and provides prognostic genetic features that refine risk stratification and will be incorporated into prospective trials.
Topics: Adolescent; Adult; Biomarkers, Tumor; Child; Child, Preschool; DNA Mutational Analysis; Databases, Genetic; Disease Progression; Female; Gene Amplification; Gene Deletion; Gene Expression Profiling; Genetic Predisposition to Disease; Genomics; Humans; INDEL Mutation; Infant; Infant, Newborn; Male; Phenotype; Predictive Value of Tests; Progression-Free Survival; Rhabdomyosarcoma, Alveolar; Rhabdomyosarcoma, Embryonal; Risk Assessment; Risk Factors; Time Factors; Transcriptome; United Kingdom; United States; Young Adult
PubMed: 34166060
DOI: 10.1200/JCO.20.03060 -
Science Translational Medicine Jul 2022Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood...
Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic Paired Box 3-Forkhead Box O1 (PAX3-FOXO1) fusion protein, which governs a core regulatory circuitry transcription factor network. Here, we show that the histone lysine demethylase 4B (KDM4B) is a therapeutic vulnerability for PAX3-FOXO1 RMS. Genetic and pharmacologic inhibition of KDM4B substantially delayed tumor growth. Suppression of KDM4 proteins inhibited the expression of core oncogenic transcription factors and caused epigenetic alterations of PAX3-FOXO1-governed superenhancers. Combining KDM4 inhibition with cytotoxic chemotherapy led to tumor regression in preclinical PAX3-FOXO1 RMS subcutaneous xenograft models. In summary, we identified a targetable mechanism required for maintenance of the PAX3-FOXO1-related transcription factor network, which may translate to a therapeutic approach for fusion-positive RMS.
Topics: Carcinogenesis; Cell Line, Tumor; Child; Forkhead Box Protein O1; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; Humans; Jumonji Domain-Containing Histone Demethylases; Oncogene Proteins, Fusion; PAX3 Transcription Factor; Paired Box Transcription Factors; Rhabdomyosarcoma; Rhabdomyosarcoma, Alveolar
PubMed: 35857643
DOI: 10.1126/scitranslmed.abq2096 -
Nature Cancer Aug 2022Rhabdomyosarcoma (RMS) is a common childhood cancer that shares features with developing skeletal muscle. Yet, the conservation of cellular hierarchy with human muscle...
Rhabdomyosarcoma (RMS) is a common childhood cancer that shares features with developing skeletal muscle. Yet, the conservation of cellular hierarchy with human muscle development and the identification of molecularly defined tumor-propagating cells has not been reported. Using single-cell RNA-sequencing, DNA-barcode cell fate mapping and functional stem cell assays, we uncovered shared tumor cell hierarchies in RMS and human muscle development. We also identified common developmental stages at which tumor cells become arrested. Fusion-negative RMS cells resemble early myogenic cells found in embryonic and fetal development, while fusion-positive RMS cells express a highly specific gene program found in muscle cells transiting from embryonic to fetal development at 7-7.75 weeks of age. Fusion-positive RMS cells also have neural pathway-enriched states, suggesting less-rigid adherence to muscle-lineage hierarchies. Finally, we identified a molecularly defined tumor-propagating subpopulation in fusion-negative RMS that shares remarkable similarity to bi-potent, muscle mesenchyme progenitors that can make both muscle and osteogenic cells.
Topics: Child; Humans; Muscle, Skeletal; Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal; Single-Cell Analysis; Stem Cells
PubMed: 35982179
DOI: 10.1038/s43018-022-00414-w -
Clinical Cancer Research : An Official... Dec 2022In many cancers, nivolumab in combination with ipilimumab improves response rates compared with either agent alone, but the combination has not been evaluated in...
PURPOSE
In many cancers, nivolumab in combination with ipilimumab improves response rates compared with either agent alone, but the combination has not been evaluated in childhood cancer. We conducted a phase I/II trial of nivolumab plus ipilimumab in children and young adults with recurrent/refractory solid tumors.
PATIENTS AND METHODS
ADVL1412, Part C assessed safety of nivolumab plus ipilimumab at two dose levels (DL): DL1 1 mg/kg of each drug and DL2 3 mg/kg nivolumab plus 1 mg/kg ipilimumab. Part D evaluated response at the recommended phase II dose (RP2D) in Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma. Part E tested DL3 (1 mg/kg nivolumab plus 3 mg/kg ipilimumab) in Ewing sarcoma and rhabdomyosarcoma. Tumor response was measured using RECIST v1.1. Pharmacokinetics and PD-L1 expression on archival tissues were assessed.
RESULTS
Fifty-five eligible patients enrolled. Based on safety, tolerability, and similar drug exposure to the same doses administered in adults, DL2 was defined as the pediatric RP2D. Among 41 patients treated at the RP2D, 2 patients experienced dose-limiting toxicities during cycle 1, and 4 patients experienced toxicities beyond that period. Two patients had clinically significant sustained partial responses (1 rhabdomyosarcoma, 1 Ewing sarcoma) and 4 had stable disease. Among 8 patients treated at DL3, 3 dose-limiting toxicities (DLT) occurred, all immune-related adverse events; no objective responses were observed.
CONCLUSIONS
The RP2D of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) is well tolerated in children and young adults with solid tumors and shows some clinical activity. Increased dose of ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) was associated with increased toxicity without clinical benefit.
Topics: Humans; Young Adult; Child; Ipilimumab; Nivolumab; Sarcoma, Ewing; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Rhabdomyosarcoma
PubMed: 36190525
DOI: 10.1158/1078-0432.CCR-22-2164 -
Oncology Letters Feb 2018Sarcomas arise from primitive mesenchymal cells, which are classified, into two main groups: Bone and soft tissue sarcomas. We have searched all-important electronic...
Sarcomas arise from primitive mesenchymal cells, which are classified, into two main groups: Bone and soft tissue sarcomas. We have searched all-important electronic databases including Google scholar and PubMed for the collection of latest literature pertaining to pediatric sarcomas. Latest literature confirmed that these tumors are relatively rare and represent only 1% of all malignancies but they have higher incidence in children. Pediatric sarcomas comprise about 13% of all pediatric malignancies and are ranked third in childhood cancers. The highest incidence rates are reported among rhabdomyosarcoma, osteosarcoma and Ewing's sarcomas in children. All of these neoplasms often display highly aggressive behavior with tendency to form metastases. Important globally used management avenues include surgery with systemic chemotherapy and have success rate of 70% at 5-years. Furthermore, in the cases of advanced stages, the prognosis is poor, chances of treatment failure and recurrence are quite high. Utilization of cancer stem cells is the latest approach with great potential in management of above pathological state. The present review article discuss all-important aspects of commonly found pediatric sarcomas throughout the world.
PubMed: 29434830
DOI: 10.3892/ol.2017.7467 -
Science Advances Feb 2023Rhabdomyosarcoma (RMS) is a group of pediatric cancers with features of developing skeletal muscle. The cellular hierarchy and mechanisms leading to developmental arrest...
Rhabdomyosarcoma (RMS) is a group of pediatric cancers with features of developing skeletal muscle. The cellular hierarchy and mechanisms leading to developmental arrest remain elusive. Here, we combined single-cell RNA sequencing, mass cytometry, and high-content imaging to resolve intratumoral heterogeneity of patient-derived primary RMS cultures. We show that the aggressive alveolar RMS (aRMS) subtype contains plastic muscle stem-like cells and cycling progenitors that drive tumor growth, and a subpopulation of differentiated cells that lost its proliferative potential and correlates with better outcomes. While chemotherapy eliminates cycling progenitors, it enriches aRMS for muscle stem-like cells. We screened for drugs hijacking aRMS toward clinically favorable subpopulations and identified a combination of RAF and MEK inhibitors that potently induces myogenic differentiation and inhibits tumor growth. Overall, our work provides insights into the developmental states underlying aRMS aggressiveness, chemoresistance, and progression and identifies the RAS pathway as a promising therapeutic target.
Topics: Child; Humans; Rhabdomyosarcoma, Alveolar; Rhabdomyosarcoma; Muscle, Skeletal; Cell Differentiation; Antineoplastic Agents; Cell Line, Tumor
PubMed: 36753540
DOI: 10.1126/sciadv.ade9238 -
Journal of Clinical Medicine May 2021Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, yet little is known about its etiology. Studies that examine either environmental exposures or... (Review)
Review
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, yet little is known about its etiology. Studies that examine either environmental exposures or germline genetic predisposition in RMS have begun to identify factors that contribute to this malignancy. Here, we summarize epidemiological reports of RMS incidence in terms of several factors, including age at diagnosis, biological sex, and geographic location. We then describe findings from association studies, which explore the role of parental exposures, birth and perinatal characteristics, and childhood exposures in RMS. Further, we discuss RMS predisposition syndromes and large-scale sequencing studies that have further identified RMS-associated genes. Finally, we propose future directions of study, which aim to advance our understanding of the origin of RMS and can provide knowledge for novel RMS therapies.
PubMed: 34065162
DOI: 10.3390/jcm10092028