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Journal of Medical Case Reports Jan 2021The importance of this paper is to help to emphasize the importance of chemotherapy for children with pure intratesticular rhabdomyosarcoma after radical inguinal... (Review)
Review
BACKGROUND
The importance of this paper is to help to emphasize the importance of chemotherapy for children with pure intratesticular rhabdomyosarcoma after radical inguinal orchiectomy is done as first treatment of rhabdomyosarcoma. The information provided in this paper about the follow-up outcomes of the patient described in this paper, it highlights that, recurrence and even metastasis of intratesticular rhabdomyosarcoma in children are more likely to occur if surgery it not combined with chemotherapy.
CASE PRESENTATION
Herein, we present a 6-year old African male child with a 3 months history of a painless right intratesticular tumour. The tumour was poorly vascularized and was in continuity with the spermatic cord. Pelvic computer tomography (CT) scan showed a heterogeneous mass with well-defined margins without microcalcification and multiple bilateral inguinal enlarged lymph nodes were noticed without pelvic lymphadenopathy. The tumour measured 3.8 × 2.8 × 3.9 cm. The tumour marker panel showed: lactate dehydrogenase of (472 UI/l), alpha-fetoprotein (1.43 UI/ml) and human chorionic gonadotrophin beta (2.9 mUI/ml). Microscopically, the tumour was composed of small to medium size undifferentiated cells. These were oval to spindle, hyperchromatic cells to stromal myxoid degeneration were noted. Tunica albuginea and rete testis both were infiltrated by tumour. The tumour showed high mitotic count which measured 50 mitoses per 10 High Power Field (HPF). The diagnosis of rhabdomyosarcoma (RMS) was confirmed by immunohistochemistry (IHC) testing using myoD antibody which showed strong and diffuse intranuclear staining of the tumour cells. Currently, he is on cyclophosphamide and vincristine chemotherapy regime and his condition has improved much.
CONCLUSIONS
The experience obtained from the index case is crucial for the management of patients with intratesticular rhabdomyosarcoma which should always make sure that radical inguinal orchiectomy is covered by chemotherapy and/or radiotherapy. This will potentially lower the possibilities of recurrence and/or metastasis of the tumour, hence improving the prognosis of the patients. We report the clinical, radiological, and laboratory characteristics as well as the outcome of the patient.
Topics: Child; Cyclophosphamide; Humans; Male; Neoplasm Recurrence, Local; Orchiectomy; Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal; Testicular Neoplasms
PubMed: 33516251
DOI: 10.1186/s13256-020-02599-z -
International Journal of Molecular... Aug 2022Uterine fibroids (UFs) are the most common benign tumors of female genital diseases, unlike uterine leiomyosarcoma (LMS), a rare and aggressive uterine cancer. This... (Review)
Review
Uterine fibroids (UFs) are the most common benign tumors of female genital diseases, unlike uterine leiomyosarcoma (LMS), a rare and aggressive uterine cancer. This narrative review aims to discuss the biology and diagnosis of LMS and, at the same time, their differential diagnosis, in order to distinguish the biological and molecular origins. The authors performed a Medline and PubMed search for the years 1990-2022 using a combination of keywords on the topics to highlight the many genes and proteins involved in the pathogenesis of LMS. The mutation of these genes, in addition to the altered expression and functions of their enzymes, are potentially biomarkers of uterine LMS. Thus, the use of this molecular and protein information could favor differential diagnosis and personalized therapy based on the molecular characteristics of LMS tissue, leading to timely diagnoses and potential better outcomes for patients.
Topics: Female; Humans; Leiomyoma; Leiomyosarcoma; Pelvic Neoplasms; Uterine Neoplasms; Uterus
PubMed: 36077127
DOI: 10.3390/ijms23179728 -
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 -
Human Reproduction (Oxford, England) Sep 2022What are the cellular composition and single-cell transcriptomic differences between myometrium and leiomyomas as defined by single-cell RNA sequencing?
STUDY QUESTION
What are the cellular composition and single-cell transcriptomic differences between myometrium and leiomyomas as defined by single-cell RNA sequencing?
SUMMARY ANSWER
We discovered cellular heterogeneity in smooth muscle cells (SMCs), fibroblast and endothelial cell populations in both myometrium and leiomyoma tissues.
WHAT IS KNOWN ALREADY
Previous studies have shown the presence of SMCs, fibroblasts, endothelial cells and immune cells in myometrium and leiomyomas. However, there is no information on the cellular heterogeneity in these tissues and the transcriptomic differences at the single-cell level between these tissues.
STUDY DESIGN, SIZE, DURATION
We collected five leiomyoma and five myometrium samples from a total of eight patients undergoing hysterectomy. We then performed single-cell RNA sequencing to generate a cell atlas for both tissues. We utilized our single-cell sequencing data to define cell types, compare cell types by tissue type (leiomyoma versus myometrium) and determine the transcriptional changes at a single-cell resolution between leiomyomas and myometrium. Additionally, we performed MED12-variant analysis at the single-cell level to determine the genotype heterogeneity within leiomyomas.
PARTICIPANTS/MATERIALS, SETTING, METHODS
We collected five MED12-variant positive leiomyomas and five myometrium samples from a total of eight patients. We then performed single-cell RNA sequencing on freshly isolated single-cell preparations. Histopathological assessment confirmed the identity of the samples. Sanger sequencing was performed to confirm the presence of the MED12 variant in leiomyomas.
MAIN RESULTS AND ROLE OF CHANCE
Our data revealed previously unknown heterogeneity in the SMC, fibroblast cell and endothelial cell populations of myometrium and leiomyomas. We discovered the presence of two different lymphatic endothelial cell populations specific to uterine leiomyomas. We showed that both myometrium and MED12-variant leiomyomas are relatively similar in cellular composition but differ in cellular transcriptomic profiles. We found that fibroblasts influence the leiomyoma microenvironment through their interactions with endothelial cells, immune cells and SMCs. Variant analysis at the single-cell level revealed the presence of both MED12 variants as well as the wild-type MED12 allele in SMCs of leiomyomatous tissue. These results indicate genotype heterogeneity of cellular composition within leiomyomas.
LARGE SCALE DATA
The datasets are available in the NCBI Gene Expression Omnibus (GEO) using GSE162122.
LIMITATIONS, REASONS FOR CAUTION
Our study focused on MED12-variant positive leiomyomas for single-cell RNA sequencing analyses. Leiomyomas carrying other genetic rearrangements may differ in their cellular composition and transcriptomic profiles.
WIDER IMPLICATIONS FOR THE FINDINGS
Our study provides a cellular atlas for myometrium and MED12-variant positive leiomyomas as defined by single-cell RNA sequencing. Our analysis provides significant insight into the differences between myometrium and leiomyomas at the single-cell level and reveals hitherto unknown genetic heterogeneity in multiple cell types within human leiomyomas. Our results will be important for future studies into the origin and growth of human leiomyomas.
STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by funding from the National Institute of Child Health and Human Development (HD098580 and HD088629). The authors declare no competing interests.
Topics: Endothelial Cells; Female; Humans; Leiomyoma; Mutation; Myometrium; Single-Cell Analysis; Tumor Microenvironment; Uterine Neoplasms
PubMed: 36001050
DOI: 10.1093/humrep/deac183 -
Pediatric Blood & Cancer Apr 2022Children and adolescents with rhabdomyosarcoma (RMS) comprise a heterogeneous population with variable overall survival rates ranging between approximately 6% and 100%... (Review)
Review
Children and adolescents with rhabdomyosarcoma (RMS) comprise a heterogeneous population with variable overall survival rates ranging between approximately 6% and 100% depending on defined risk factors. Although the risk stratification of patients has been refined across five decades of collaborative group studies, molecular prognostic biomarkers beyond FOXO1 fusion status have yet to be incorporated prospectively in upfront risk-based therapy assignments. This review describes the evolution of risk-based therapy and the current risk stratification, defines a new risk stratification incorporating novel biomarkers, and provides the rationale for the current and upcoming Children's Oncology Group RMS studies.
Topics: Adolescent; Child; Gene Fusion; Humans; Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal; Risk Assessment; Risk Factors
PubMed: 35129294
DOI: 10.1002/pbc.29511 -
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 -
Critical Reviews in Oncology/hematology Apr 2023Leiomyosarcoma (LMS) is a soft tissue sarcoma of smooth muscle origin that can arise in multiple anatomical sites and is broadly classified as extra-uterine LMS or... (Review)
Review
Leiomyosarcoma (LMS) is a soft tissue sarcoma of smooth muscle origin that can arise in multiple anatomical sites and is broadly classified as extra-uterine LMS or uterine LMS. There is substantial interpatient heterogeneity within this histological subtype, and despite multi-modal therapy, clinical management remains challenging with poor patient prognosis and few new therapies available. Here we discuss the current treatment landscape of LMS in both the localised and advanced disease setting. We further describe the latest advances in our evolving understanding of the genetics and biology of this group of heterogeneous diseases and summarise the key studies delineating the mechanisms of acquired and intrinsic chemotherapy resistance in this histological subtype. We conclude by providing a perspective on how novel targeted agents such as PARP inhibitors may usher in a new paradigm of biomarker-driven therapies that will ultimately impact the outcomes of patients with LMS.
Topics: Female; Humans; Leiomyosarcoma; Sarcoma; Antineoplastic Agents; Uterine Neoplasms; Biology
PubMed: 36893945
DOI: 10.1016/j.critrevonc.2023.103955 -
Developmental Cell May 2022Rhabdomyosarcoma (RMS) is a pediatric cancer with features of skeletal muscle; patients with unresectable or metastatic RMS fare poorly due to high rates of disease...
Rhabdomyosarcoma (RMS) is a pediatric cancer with features of skeletal muscle; patients with unresectable or metastatic RMS fare poorly due to high rates of disease recurrence. Here, we use single-cell and single-nucleus RNA sequencing to show that RMS tumors recapitulate the spectrum of embryonal myogenesis. Using matched patient samples from a clinical trial and orthotopic patient-derived xenografts (O-PDXs), we show that chemotherapy eliminates the most proliferative component with features of myoblasts within embryonal RMS; after treatment, the immature population with features of paraxial mesoderm expands to reconstitute the developmental hierarchy of the original tumor. We discovered that this paraxial mesoderm population is dependent on EGFR signaling and is sensitive to EGFR inhibitors. Taken together, these data serve as a proof of concept that targeting each developmental state in embryonal RMS is an effective strategy for improving outcomes by preventing disease recurrence.
Topics: Child; Drug Resistance; ErbB Receptors; Humans; Muscle Development; Neoplasm Recurrence, Local; Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal
PubMed: 35483358
DOI: 10.1016/j.devcel.2022.04.003 -
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 -
European Journal of Cancer (Oxford,... Sep 2022Rhabdomyosarcomas (RMSs) are the most common soft tissue sarcomas in children/adolescents less than 18 years of age with an annual incidence of 1-2/million.... (Review)
Review
Molecular testing of rhabdomyosarcoma in clinical trials to improve risk stratification and outcome: A consensus view from European paediatric Soft tissue sarcoma Study Group, Children's Oncology Group and Cooperative Weichteilsarkom-Studiengruppe.
Rhabdomyosarcomas (RMSs) are the most common soft tissue sarcomas in children/adolescents less than 18 years of age with an annual incidence of 1-2/million. Inter/intra-tumour heterogeneity raise challenges in clinical, pathological and biological research studies. Risk stratification in European and North American clinical trials previously relied on clinico-pathological features, but now, incorporates PAX3/7-FOXO1-fusion gene status in the place of alveolar histology. International working groups propose a coordinated approach through the INternational Soft Tissue SaRcoma ConsorTium to evaluate the specific genetic abnormalities and generate and integrate molecular and clinical data related to patients with RMS across different trial settings. We review relevant data and present a consensus view on what molecular features should be assessed. In particular, we recommend the assessment of the MYOD1-LR122R mutation for risk escalation, as it has been associated with poor outcomes in spindle/sclerosing RMS and rare RMS with classic embryonal histopathology. The prospective analyses of rare fusion genes beyond PAX3/7-FOXO1 will generate new data linked to outcomes and assessment of TP53 mutations and CDK4 amplification may confirm their prognostic value. Pathogenic/likely pathogenic germline variants in TP53 and other cancer predisposition genes should also be assessed. DNA/RNA profiling of tumours at diagnosis/relapse and serial analyses of plasma samples is recommended where possible to validate potential molecular biomarkers, identify new biomarkers and assess how liquid biopsy analyses can have the greatest benefit. Together with the development of new molecularly-derived therapeutic strategies that we review, a synchronised international approach is expected to enhance progress towards improved treatment assignment, management and outcomes for patients with RMS.
Topics: Adolescent; Child; Consensus; Humans; Molecular Diagnostic Techniques; Neoplasm Recurrence, Local; Prospective Studies; Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal; Risk Assessment; Soft Tissue Neoplasms
PubMed: 35839732
DOI: 10.1016/j.ejca.2022.05.036